chr19-36006456-C-G

Variant names:

• chr19-36006456-C-G
• rs2285422
• NM_001039876.3:c.834G>C

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_001039876.3(SYNE4):​c.834G>C​(p.Gln278His) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.94 in 1,612,406 control chromosomes in the GnomAD database, including 713,595 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.95 (68878 hom., cov: 31)
  • Exomes 𝑓: 0.94 (644717 hom.)
• Consequence: SYNE4 NM_001039876.3 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:5
• Conservation: PhyloP100: -0.167
• Publications: 31 publications found

Genes affected

SYNE4 (HGNC:26703): (spectrin repeat containing nuclear envelope family member 4) This gene is a member of the nesprin family of genes, that encode KASH (Klarsicht, Anc-1, Syne Homology) domain-containing proteins. In addition to the KASH domain, this protein also contains a coiled-coil and leucine zipper region, a spectrin repeat, and a kinesin-1 binding region. This protein localizes to the outer nuclear membrane, and is part of the linker of nucleoskeleton and cytoskeleton (LINC) complex in the nuclear envelope. LINC complexes are formed by SUN (Sad1, UNC-84)-KASH pairs, and are thought to mechanically couple nuclear components to the cytoskeleton. Mutations in this gene have been associated with progressive high-frequency hearing loss. The absence of this protein in mice also caused hearing loss, and changes in hair cell morphology in the ears. Alternative splicing results in multiple transcript variants encoding different isoforms. [provided by RefSeq, Aug 2015]

SYNE4 Gene-Disease associations (from GenCC):

• autosomal recessive nonsyndromic hearing loss 76

  Inheritance: AR Classification: STRONG Submitted by: PanelApp Australia, Labcorp Genetics (formerly Invitae)
• nonsyndromic genetic hearing loss

  Inheritance: AR Classification: MODERATE Submitted by: ClinGen
• hearing loss, autosomal recessive

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Benign. The variant received -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=6.1539436E-7).
• BP6: Variant 19-36006456-C-G is Benign according to our data. Variant chr19-36006456-C-G is described in CliVar as Benign. Clinvar id is 227091.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr19-36006456-C-G is described in CliVar as Benign. Clinvar id is 227091.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr19-36006456-C-G is described in CliVar as Benign. Clinvar id is 227091.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr19-36006456-C-G is described in CliVar as Benign. Clinvar id is 227091.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr19-36006456-C-G is described in CliVar as Benign. Clinvar id is 227091.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr19-36006456-C-G is described in CliVar as Benign. Clinvar id is 227091.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr19-36006456-C-G is described in CliVar as Benign. Clinvar id is 227091.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr19-36006456-C-G is described in CliVar as Benign. Clinvar id is 227091.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr19-36006456-C-G is described in CliVar as Benign. Clinvar id is 227091.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr19-36006456-C-G is described in CliVar as Benign. Clinvar id is 227091.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr19-36006456-C-G is described in CliVar as Benign. Clinvar id is 227091.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr19-36006456-C-G is described in CliVar as Benign. Clinvar id is 227091.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr19-36006456-C-G is described in CliVar as Benign. Clinvar id is 227091.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr19-36006456-C-G is described in CliVar as Benign. Clinvar id is 227091.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr19-36006456-C-G is described in CliVar as Benign. Clinvar id is 227091.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr19-36006456-C-G is described in CliVar as Benign. Clinvar id is 227091.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr19-36006456-C-G is described in CliVar as Benign. Clinvar id is 227091.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr19-36006456-C-G is described in CliVar as Benign. Clinvar id is 227091.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr19-36006456-C-G is described in CliVar as Benign. Clinvar id is 227091.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr19-36006456-C-G is described in CliVar as Benign. Clinvar id is 227091.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr19-36006456-C-G is described in CliVar as Benign. Clinvar id is 227091.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr19-36006456-C-G is described in CliVar as Benign. Clinvar id is 227091.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr19-36006456-C-G is described in CliVar as Benign. Clinvar id is 227091.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr19-36006456-C-G is described in CliVar as Benign. Clinvar id is 227091.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr19-36006456-C-G is described in CliVar as Benign. Clinvar id is 227091.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr19-36006456-C-G is described in CliVar as Benign. Clinvar id is 227091.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr19-36006456-C-G is described in CliVar as Benign. Clinvar id is 227091.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr19-36006456-C-G is described in CliVar as Benign. Clinvar id is 227091.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr19-36006456-C-G is described in CliVar as Benign. Clinvar id is 227091.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr19-36006456-C-G is described in CliVar as Benign. Clinvar id is 227091.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr19-36006456-C-G is described in CliVar as Benign. Clinvar id is 227091.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr19-36006456-C-G is described in CliVar as Benign. Clinvar id is 227091.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr19-36006456-C-G is described in CliVar as Benign. Clinvar id is 227091.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr19-36006456-C-G is described in CliVar as Benign. Clinvar id is 227091.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr19-36006456-C-G is described in CliVar as Benign. Clinvar id is 227091.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.979 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SYNE4	NM_001039876.3	c.834G>C	p.Gln278His	missense_variant	Exon 5 of 8	ENST00000324444.9	NP_001034965.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
SYNE4	ENST00000324444.9	c.834G>C	p.Gln278His	missense_variant	Exon 5 of 8	5	NM_001039876.3	ENSP00000316130.3

Frequencies

GnomAD3 genomes AF: 0.950 AC: 144518 AN: 152078 Hom.: 68818 Cov.: 31

Gnomad AFR AF: 0.987

Gnomad AMI AF: 0.911

Gnomad AMR AF: 0.953

Gnomad ASJ AF: 0.904

Gnomad EAS AF: 0.805

Gnomad SAS AF: 0.843

Gnomad FIN AF: 0.951

Gnomad MID AF: 0.962

Gnomad NFE AF: 0.949

Gnomad OTH AF: 0.954

GnomAD2 exomes AF: 0.927 AC: 228734 AN: 246814 AF XY: 0.924

Gnomad AFR exome AF: 0.990

Gnomad AMR exome AF: 0.947

Gnomad ASJ exome AF: 0.906

Gnomad EAS exome AF: 0.794

Gnomad FIN exome AF: 0.953

Gnomad NFE exome AF: 0.948

Gnomad OTH exome AF: 0.940

GnomAD4 exome AF: 0.939 AC: 1371128 AN: 1460210 Hom.: 644717 Cov.: 82 AF XY: 0.937 AC XY: 680221 AN XY: 726308

African (AFR) AF: 0.991 AC: 33166 AN: 33452

American (AMR) AF: 0.949 AC: 42305 AN: 44596

Ashkenazi Jewish (ASJ) AF: 0.905 AC: 23580 AN: 26066

East Asian (EAS) AF: 0.808 AC: 32046 AN: 39674

South Asian (SAS) AF: 0.862 AC: 74134 AN: 86014

European-Finnish (FIN) AF: 0.954 AC: 50862 AN: 53316

Middle Eastern (MID) AF: 0.953 AC: 5024 AN: 5270

European-Non Finnish (NFE) AF: 0.948 AC: 1053653 AN: 1111550

Other (OTH) AF: 0.935 AC: 56358 AN: 60272

GnomAD4 genome AF: 0.950 AC: 144638 AN: 152196 Hom.: 68878 Cov.: 31 AF XY: 0.948 AC XY: 70536 AN XY: 74406

African (AFR) AF: 0.987 AC: 40998 AN: 41540

American (AMR) AF: 0.953 AC: 14580 AN: 15304

Ashkenazi Jewish (ASJ) AF: 0.904 AC: 3139 AN: 3472

East Asian (EAS) AF: 0.805 AC: 4143 AN: 5144

South Asian (SAS) AF: 0.843 AC: 4065 AN: 4824

European-Finnish (FIN) AF: 0.951 AC: 10099 AN: 10616

Middle Eastern (MID) AF: 0.963 AC: 283 AN: 294

European-Non Finnish (NFE) AF: 0.949 AC: 64489 AN: 67982

Other (OTH) AF: 0.954 AC: 2013 AN: 2110

Alfa AF: 0.945 Hom.: 22031

Bravo AF: 0.953

TwinsUK AF: 0.948 AC: 3517

ALSPAC AF: 0.948 AC: 3654

ESP6500AA AF: 0.991 AC: 3824

ESP6500EA AF: 0.951 AC: 7830

ExAC AF: 0.927 AC: 111943

Asia WGS AF: 0.848 AC: 2950 AN: 3478

EpiCase AF: 0.949

EpiControl AF: 0.951

ClinVar

Significance: Benign

Submissions summary: Benign:5

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:2

May 09, 2017

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease. -

Nov 24, 2014

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Gln278His in exon 5 of SYNE4: This variant is not expected to have clinical sign ificance because it has been identified in 4.9% (402/8232) of European American chromosomes from a broad population by the NHLBI Exome Sequencing Project (http: //evs.gs.washington.edu/EVS; dbSNP rs2285422). -

not provided Benign:2

Feb 03, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Autosomal recessive nonsyndromic hearing loss 76 Benign:1

Jul 15, 2021

Genome-Nilou Lab

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.074
BayesDel_addAF	Benign	-0.78	T
BayesDel_noAF	Benign	-0.75
CADD	Benign	0.73
DANN	Benign	0.67
DEOGEN2	Benign	0.0029	T;T;.
Eigen	Benign	-1.5
Eigen_PC	Benign	-1.4
FATHMM_MKL	Benign	0.0034	N
LIST_S2	Benign	0.19	.;T;T
MetaRNN	Benign	6.2e-7	T;T;T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	-1.6	N;N;.
PhyloP100		-0.17
PrimateAI	Benign	0.35	T
PROVEAN	Benign	1.6	N;.;N
REVEL	Benign	0.050
Sift	Benign	1.0	T;.;T
Sift4G	Benign	1.0	T;.;T
Polyphen		0.0	B;B;B
Vest4		0.034
MutPred		0.080		Gain of catalytic residue at Q278 (P = 0.0267);Gain of catalytic residue at Q278 (P = 0.0267);.;
MPC		0.085
ClinPred		0.00036	T
GERP RS		-1.0
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.039
gMVP		0.11
Mutation Taster		=100/0	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.0		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs2285422; hg19: chr19-36497358; COSMIC: COSV53324670; COSMIC: COSV53324670;