rs117623694

chr6-152321935-C-T

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The NM_182961.4(SYNE1):c.15918-49G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0346 in 1,608,414 control chromosomes in the GnomAD database, including 1,149 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.024 (63 hom., cov: 32)
  • Exomes 𝑓: 0.036 (1086 hom.)
• Consequence: SYNE1 NM_182961.4 intron
• Clinical Significance: Likely benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -0.370

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 Benign. Variant got -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.83).
• BP6: Variant 6-152321935-C-T is Benign according to our data. Variant chr6-152321935-C-T is described in ClinVar as [Likely_benign]. Clinvar id is 262166.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.0241 (3673/152258) while in subpopulation NFE AF= 0.0399 (2715/68014). AF 95% confidence interval is 0.0387. There are 63 homozygotes in gnomad4. There are 1643 alleles in male gnomad4 subpopulation. This position pass quality control queck.
• BS2: High AC in GnomAd at 3673 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
SYNE1	NM_182961.4	c.15918-49G>A		intron_variant		ENST00000367255.10

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
SYNE1	ENST00000367255.10	c.15918-49G>A		intron_variant		1	NM_182961.4	P1

Frequencies

GnomAD3 genomes AF: 0.0241 AC: 3673 AN: 152140 Hom.: 63 Cov.: 32

Gnomad AFR AF: 0.00714

Gnomad AMI AF: 0.0110

Gnomad AMR AF: 0.0212

Gnomad ASJ AF: 0.0236

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00415

Gnomad FIN AF: 0.0155

Gnomad MID AF: 0.00633

Gnomad NFE AF: 0.0399

Gnomad OTH AF: 0.0283

GnomAD3 exomes AF: 0.0240 AC: 6009 AN: 250290 Hom.: 102 AF XY: 0.0243 AC XY: 3287 AN XY: 135446

Gnomad AFR exome AF: 0.00662

Gnomad AMR exome AF: 0.0149

Gnomad ASJ exome AF: 0.0229

Gnomad EAS exome AF: 0.0000544

Gnomad SAS exome AF: 0.00461

Gnomad FIN exome AF: 0.0189

Gnomad NFE exome AF: 0.0392

Gnomad OTH exome AF: 0.0285

GnomAD4 exome AF: 0.0357 AC: 51960 AN: 1456156 Hom.: 1086 Cov.: 29 AF XY: 0.0347 AC XY: 25175 AN XY: 724644

Gnomad4 AFR exome AF: 0.00551

Gnomad4 AMR exome AF: 0.0156

Gnomad4 ASJ exome AF: 0.0247

Gnomad4 EAS exome AF: 0.0000252

Gnomad4 SAS exome AF: 0.00496

Gnomad4 FIN exome AF: 0.0187

Gnomad4 NFE exome AF: 0.0426

Gnomad4 OTH exome AF: 0.0291

GnomAD4 genome AF: 0.0241 AC: 3673 AN: 152258 Hom.: 63 Cov.: 32 AF XY: 0.0221 AC XY: 1643 AN XY: 74434

Gnomad4 AFR AF: 0.00712

Gnomad4 AMR AF: 0.0212

Gnomad4 ASJ AF: 0.0236

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00436

Gnomad4 FIN AF: 0.0155

Gnomad4 NFE AF: 0.0399

Gnomad4 OTH AF: 0.0280

Alfa AF: 0.0329 Hom.: 22

Bravo AF: 0.0241

Asia WGS AF: 0.00346 AC: 12 AN: 3478

ClinVar

Significance: Likely benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:1

Likely benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

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- -

not provided Benign:1

Likely benign, criteria provided, single submitter

clinical testing

GeneDx

Jun 19, 2018

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. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.83
Cadd	Benign	2.1
Dann	Benign	0.39

Splicing

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

Publications

LitVar

Other links and lift over

dbSNP: rs117623694; hg19: chr6-152643070; COSMIC: COSV55083404; COSMIC: COSV55083404;