rs74709220

Positions:

• chr6-152145443-A-C
• chr6-152145443-A-G

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.24977-1678T>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0152 in 1,571,464 control chromosomes in the GnomAD database, including 1,367 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.012 (106 hom., cov: 32)
  • Exomes 𝑓: 0.016 (1261 hom.)
• Consequence: SYNE1 NM_182961.4 intron
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 2.00

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 6-152145443-A-C is Benign according to our data. Variant chr6-152145443-A-C is described in ClinVar as [Likely_benign]. Clinvar id is 262191.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.127 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
SYNE1	NM_001347702.2	c.1510+44T>G		intron_variant		ENST00000354674.5
SYNE1	NM_182961.4	c.24977-1678T>G		intron_variant		ENST00000367255.10

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
SYNE1	ENST00000354674.5	c.1510+44T>G		intron_variant		5	NM_001347702.2
SYNE1	ENST00000367255.10	c.24977-1678T>G		intron_variant		1	NM_182961.4	P1

Frequencies

GnomAD3 genomes AF: 0.0125 AC: 1907 AN: 152128 Hom.: 107 Cov.: 32

Gnomad AFR AF: 0.00113

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00275

Gnomad ASJ AF: 0.0305

Gnomad EAS AF: 0.120

Gnomad SAS AF: 0.136

Gnomad FIN AF: 0.00631

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00500

Gnomad OTH AF: 0.0144

GnomAD3 exomes AF: 0.0300 AC: 7473 AN: 249170 Hom.: 462 AF XY: 0.0352 AC XY: 4745 AN XY: 134672

Gnomad AFR exome AF: 0.000871

Gnomad AMR exome AF: 0.00204

Gnomad ASJ exome AF: 0.0283

Gnomad EAS exome AF: 0.120

Gnomad SAS exome AF: 0.136

Gnomad FIN exome AF: 0.00551

Gnomad NFE exome AF: 0.00485

Gnomad OTH exome AF: 0.0218

GnomAD4 exome AF: 0.0155 AC: 22016 AN: 1419218 Hom.: 1261 Cov.: 23 AF XY: 0.0193 AC XY: 13709 AN XY: 708654

Gnomad4 AFR exome AF: 0.00114

Gnomad4 AMR exome AF: 0.00222

Gnomad4 ASJ exome AF: 0.0288

Gnomad4 EAS exome AF: 0.127

Gnomad4 SAS exome AF: 0.131

Gnomad4 FIN exome AF: 0.00594

Gnomad4 NFE exome AF: 0.00309

Gnomad4 OTH exome AF: 0.0211

GnomAD4 genome AF: 0.0125 AC: 1902 AN: 152246 Hom.: 106 Cov.: 32 AF XY: 0.0147 AC XY: 1094 AN XY: 74448

Gnomad4 AFR AF: 0.00113

Gnomad4 AMR AF: 0.00275

Gnomad4 ASJ AF: 0.0305

Gnomad4 EAS AF: 0.119

Gnomad4 SAS AF: 0.135

Gnomad4 FIN AF: 0.00631

Gnomad4 NFE AF: 0.00500

Gnomad4 OTH AF: 0.0156

Alfa AF: 0.00940 Hom.: 4

Bravo AF: 0.00868

Asia WGS AF: 0.126 AC: 437 AN: 3478

ClinVar

Significance: Benign/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

-

- -

not provided Benign:1

Benign, criteria provided, single submitter

clinical testing

GeneDx

Jun 28, 2018

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.81
CADD	Benign	8.1
DANN	Benign	0.60

Splicing

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

Publications

LitVar

Other links and lift over

dbSNP: rs74709220; hg19: chr6-152466578;