6-152148297-C-T

Variant names:

• chr6-152148297-C-T
• rs751624606
• NM_182961.4:c.24724G>A

Variant summary

Our verdict is Likely benign. Variant got -3 ACMG points: 0P and 3B. BP4_Moderate BS2_Supporting

The NM_182961.4(SYNE1):​c.24724G>A​(p.Asp8242Asn) variant causes a missense change. The variant allele was found at a frequency of 0.00000479 in 1,461,466 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000048 (0 hom.)
• Consequence: SYNE1 NM_182961.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 3.69

Genes affected

SYNE1 (HGNC:17089): (spectrin repeat containing nuclear envelope protein 1) This gene encodes a spectrin repeat containing protein expressed in skeletal and smooth muscle, and peripheral blood lymphocytes, that localizes to the nuclear membrane. Mutations in this gene have been associated with autosomal recessive spinocerebellar ataxia 8, also referred to as autosomal recessive cerebellar ataxia type 1 or recessive ataxia of Beauce. Alternatively spliced transcript variants encoding different isoforms have been described. [provided by RefSeq, Jul 2008]

ACMG classification

Verdict is Likely_benign. Variant got -3 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.25712907).
• BS2: High AC in GnomAdExome4 at 7 AD gene. Variant has AC lower than other variant known as pathogenic in the gene, so the strength is limited to Supporting.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SYNE1	NM_182961.4	c.24724G>A	p.Asp8242Asn	missense_variant	Exon 137 of 146	ENST00000367255.10	NP_892006.3
SYNE1	NM_001347702.2	c.1189G>A	p.Asp397Asn	missense_variant	Exon 8 of 18	ENST00000354674.5	NP_001334631.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
SYNE1	ENST00000367255.10	c.24724G>A	p.Asp8242Asn	missense_variant	Exon 137 of 146	1	NM_182961.4	ENSP00000356224.5
SYNE1	ENST00000354674.5	c.1189G>A	p.Asp397Asn	missense_variant	Exon 8 of 18	5	NM_001347702.2	ENSP00000346701.4

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD3 exomes AF: 0.0000160 AC: 4 AN: 250452 Hom.: 0 AF XY: 0.0000148 AC XY: 2 AN XY: 135324

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.0000868

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.0000328

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000479 AC: 7 AN: 1461466 Hom.: 0 Cov.: 32 AF XY: 0.00000550 AC XY: 4 AN XY: 726992

Gnomad4 AFR exome AF: 0.0000299

Gnomad4 AMR exome AF: 0.0000671

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000116

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000180

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

Bravo AF: 0.00000756

ExAC AF: 0.00000824 AC: 1

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

Autosomal recessive ataxia, Beauce type;C2751807:Emery-Dreifuss muscular dystrophy 4, autosomal dominant Uncertain:1

Nov 22, 2022

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant is present in population databases (rs751624606, gnomAD 0.009%). This sequence change replaces aspartic acid, which is acidic and polar, with asparagine, which is neutral and polar, at codon 8171 of the SYNE1 protein (p.Asp8171Asn). This variant has not been reported in the literature in individuals affected with SYNE1-related conditions. ClinVar contains an entry for this variant (Variation ID: 573152). Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Benign"; Align-GVGD: "Class C0"). In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.086
BayesDel_addAF	Benign	-0.36	T
BayesDel_noAF	Benign	-0.55
CADD	Benign	19
DANN	Uncertain	1.0
DEOGEN2	Benign	0.25	T;.;.;T;T;T;T
Eigen	Benign	-0.022
Eigen_PC	Benign	-0.037
FATHMM_MKL	Uncertain	0.93	D
LIST_S2	Uncertain	0.97	D;D;D;D;D;D;D
M_CAP	Benign	0.018	T
MetaRNN	Benign	0.26	T;T;T;T;T;T;T
MetaSVM	Benign	-1.1	T
MutationAssessor	Uncertain	2.2	M;.;.;.;.;.;.
PrimateAI	Benign	0.37	T
PROVEAN	Benign	-1.8	N;.;N;N;N;N;N
REVEL	Benign	0.090
Sift	Uncertain	0.023	D;.;T;T;D;T;T
Sift4G	Uncertain	0.052	T;D;T;T;D;T;T
Polyphen		0.66	P;.;.;.;.;.;.
Vest4		0.28
MutPred		0.21		Loss of phosphorylation at S8247 (P = 0.1411);.;.;.;.;.;.;
MVP		0.65
MPC		0.14
ClinPred		0.56	D
GERP RS		4.3
Varity_R		0.068
gMVP		0.38

Splicing

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

Publications

LitVar

Other links and lift over

dbSNP: rs751624606; hg19: chr6-152469432; COSMIC: COSV55133030; COSMIC: COSV55133030;