rs2253512

Variant names:

• chr6-152201791-G-A
• rs2253512
• NM_182961.4:c.23145+33C>T

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_182961.4(SYNE1):​c.23145+33C>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.157 in 1,613,416 control chromosomes in the GnomAD database, including 20,858 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.13 (1588 hom., cov: 32)
  • Exomes 𝑓: 0.16 (19270 hom.)
• Consequence: SYNE1 NM_182961.4 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 0.292

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=-0.81).
• BP6: Variant 6-152201791-G-A is Benign according to our data. Variant chr6-152201791-G-A is described in ClinVar as [Benign]. Clinvar id is 262185.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.167 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SYNE1	NM_182961.4	c.23145+33C>T		intron_variant	Intron 127 of 145	ENST00000367255.10	NP_892006.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
SYNE1	ENST00000367255.10	c.23145+33C>T		intron_variant	Intron 127 of 145	1	NM_182961.4	ENSP00000356224.5

Frequencies

GnomAD3 genomes AF: 0.135 AC: 20493 AN: 152028 Hom.: 1591 Cov.: 32

Gnomad AFR AF: 0.0645

Gnomad AMI AF: 0.124

Gnomad AMR AF: 0.161

Gnomad ASJ AF: 0.168

Gnomad EAS AF: 0.128

Gnomad SAS AF: 0.140

Gnomad FIN AF: 0.126

Gnomad MID AF: 0.256

Gnomad NFE AF: 0.170

Gnomad OTH AF: 0.170

GnomAD3 exomes AF: 0.149 AC: 37451 AN: 250708 Hom.: 2932 AF XY: 0.152 AC XY: 20600 AN XY: 135476

Gnomad AFR exome AF: 0.0634

Gnomad AMR exome AF: 0.129

Gnomad ASJ exome AF: 0.168

Gnomad EAS exome AF: 0.140

Gnomad SAS exome AF: 0.139

Gnomad FIN exome AF: 0.137

Gnomad NFE exome AF: 0.172

Gnomad OTH exome AF: 0.174

GnomAD4 exome AF: 0.160 AC: 233282 AN: 1461270 Hom.: 19270 Cov.: 33 AF XY: 0.160 AC XY: 116334 AN XY: 726968

Gnomad4 AFR exome AF: 0.0643

Gnomad4 AMR exome AF: 0.132

Gnomad4 ASJ exome AF: 0.174

Gnomad4 EAS exome AF: 0.129

Gnomad4 SAS exome AF: 0.139

Gnomad4 FIN exome AF: 0.139

Gnomad4 NFE exome AF: 0.167

Gnomad4 OTH exome AF: 0.161

GnomAD4 genome AF: 0.135 AC: 20495 AN: 152146 Hom.: 1588 Cov.: 32 AF XY: 0.133 AC XY: 9914 AN XY: 74368

Gnomad4 AFR AF: 0.0643

Gnomad4 AMR AF: 0.161

Gnomad4 ASJ AF: 0.168

Gnomad4 EAS AF: 0.128

Gnomad4 SAS AF: 0.141

Gnomad4 FIN AF: 0.126

Gnomad4 NFE AF: 0.170

Gnomad4 OTH AF: 0.169

Alfa AF: 0.153 Hom.: 572

Bravo AF: 0.133

Asia WGS AF: 0.142 AC: 495 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:1

-

PreventionGenetics, part of Exact Sciences

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

not provided Benign:1

Jun 14, 2018

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. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.81
CADD	Benign	3.8
DANN	Benign	0.72

Splicing

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

Publications

LitVar

Other links and lift over

dbSNP: rs2253512; hg19: chr6-152522926; COSMIC: COSV55114184;