6-152463467-G-T

Position:

• chr6-152463467-G-T

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 2P and 0B. PM2

The NM_182961.4(SYNE1):​c.1983C>A​(p.Asn661Lys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000137 in 1,461,420 control chromosomes in the GnomAD database, with no homozygous occurrence. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Synonymous variant affecting the same amino acid position (i.e. N661N) has been classified as Likely benign.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000014 (0 hom.)
• Consequence: SYNE1 NM_182961.4 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.00500

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 Uncertain_significance. Variant got 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
SYNE1	NM_182961.4	c.1983C>A	p.Asn661Lys	missense_variant	19/146	ENST00000367255.10	NP_892006.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
SYNE1	ENST00000367255.10	c.1983C>A	p.Asn661Lys	missense_variant	19/146	1	NM_182961.4	ENSP00000356224.5

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD3 exomes AF: 0.00000399 AC: 1 AN: 250938 Hom.: 0 AF XY: 0.00 AC XY: 0 AN XY: 135618

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00000882

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000137 AC: 2 AN: 1461420 Hom.: 0 Cov.: 32 AF XY: 0.00 AC XY: 0 AN XY: 727004

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000180

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	1.0
BayesDel_addAF	Benign	-0.13	T
BayesDel_noAF	Benign	-0.42
CADD	Benign	0.41
DANN	Uncertain	0.99
DEOGEN2	Uncertain	0.72	D;.;T;.;.;.;T;.
Eigen	Benign	-0.53
Eigen_PC	Benign	-0.69
FATHMM_MKL	Benign	0.71	D
LIST_S2	Uncertain	0.96	D;D;D;D;D;D;D;D
M_CAP	Benign	0.075	D
MetaRNN	Uncertain	0.51	D;D;D;D;D;D;D;D
MetaSVM	Benign	-0.40	T
MutationAssessor	Uncertain	2.6	M;.;.;M;.;M;.;.
PrimateAI	Uncertain	0.78	T
PROVEAN	Pathogenic	-4.5	D;.;D;D;D;D;D;D
REVEL	Uncertain	0.43
Sift	Uncertain	0.0020	D;.;D;D;D;D;D;D
Sift4G	Pathogenic	0.0	D;D;D;D;D;D;D;D
Polyphen		1.0	D;.;.;.;D;.;D;D
Vest4		0.84
MutPred		0.65		Gain of ubiquitination at N661 (P = 0.0258);.;.;Gain of ubiquitination at N661 (P = 0.0258);.;Gain of ubiquitination at N661 (P = 0.0258);.;Gain of ubiquitination at N661 (P = 0.0258);
MVP		0.27
MPC		0.56
ClinPred		1.0	D
GERP RS		-7.0
Varity_R		0.71
gMVP		0.81

Splicing

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

Publications

LitVar

Other links and lift over

dbSNP: rs149670417; hg19: chr6-152784602;