rs2285422

Positions:

• chr19-36006456-C-G

Variant summary

Our verdict is Benign. Variant got -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. 14/20 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:4
• Conservation: PhyloP100: -0.167

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]

ACMG classification

Verdict is Benign. Variant got -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 ClinVar 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/exons	MANE	UniProt
SYNE4	NM_001039876.3	c.834G>C	p.Gln278His	missense_variant	5/8	ENST00000324444.9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
SYNE4	ENST00000324444.9	c.834G>C	p.Gln278His	missense_variant	5/8	5	NM_001039876.3	P2

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

GnomAD3 exomes AF: 0.927 AC: 228734 AN: 246814 Hom.: 106346 AF XY: 0.924 AC XY: 123911 AN XY: 134106

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 SAS exome AF: 0.857

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

Gnomad4 AFR exome AF: 0.991

Gnomad4 AMR exome AF: 0.949

Gnomad4 ASJ exome AF: 0.905

Gnomad4 EAS exome AF: 0.808

Gnomad4 SAS exome AF: 0.862

Gnomad4 FIN exome AF: 0.954

Gnomad4 NFE exome AF: 0.948

Gnomad4 OTH exome AF: 0.935

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

Gnomad4 AFR AF: 0.987

Gnomad4 AMR AF: 0.953

Gnomad4 ASJ AF: 0.904

Gnomad4 EAS AF: 0.805

Gnomad4 SAS AF: 0.843

Gnomad4 FIN AF: 0.951

Gnomad4 NFE AF: 0.949

Gnomad4 OTH AF: 0.954

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:4

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:2

Benign, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Nov 24, 2014	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). -
Benign, criteria provided, single submitter	clinical testing	GeneDx	May 09, 2017	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. -

Autosomal recessive nonsyndromic hearing loss 76 Benign:1

Benign, criteria provided, single submitter

clinical testing

Genome-Nilou Lab

Jul 15, 2021

- -

not provided Benign:1

Benign, criteria provided, single submitter

clinical testing

Invitae

Feb 01, 2024

- -

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
MetaRNN	Benign	6.2e-7	T;T;T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	-1.6	N;N;.
MutationTaster	Benign	1.0	P;P
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

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

Publications

LitVar

Other links and lift over

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