NM_182961.4:c.3505-39A>C

Variant names:

• chr6-152447661-T-G
• rs502268
• NM_182961.4:c.3505-39A>C

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_182961.4(SYNE1):​c.3505-39A>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.449 in 1,612,256 control chromosomes in the GnomAD database, including 169,975 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.52 (22183 hom., cov: 33)
  • Exomes 𝑓: 0.44 (147792 hom.)
• Consequence: SYNE1 NM_182961.4 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:5
• Conservation: PhyloP100: -0.462
• Publications: 8 publications found

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]

SYNE1 Gene-Disease associations (from GenCC):

• autosomal recessive ataxia, Beauce type

  Inheritance: AR Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Ambry Genetics, G2P, Orphanet, Laboratory for Molecular Medicine, Labcorp Genetics (formerly Invitae)
• arthrogryposis multiplex congenita 3, myogenic type

  Inheritance: AR Classification: STRONG Submitted by: Labcorp Genetics (formerly Invitae)
• Emery-Dreifuss muscular dystrophy 4, autosomal dominant

  Inheritance: AD Classification: MODERATE, LIMITED Submitted by: Ambry Genetics, Labcorp Genetics (formerly Invitae), Illumina
• autosomal dominant Emery-Dreifuss muscular dystrophy

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• autosomal recessive myogenic arthrogryposis multiplex congenita

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Benign. The variant received -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.77).
• BP6: Variant 6-152447661-T-G is Benign according to our data. Variant chr6-152447661-T-G is described in ClinVar as Benign. ClinVar VariationId is 262196.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.741 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_182961.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SYNE1	NM_182961.4	MANE Select	c.3505-39A>C		intron	N/A	NP_892006.3
	SYNE1	NM_033071.5		c.3526-39A>C		intron	N/A	NP_149062.2

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SYNE1	ENST00000367255.10	TSL:1 MANE Select	c.3505-39A>C		intron	N/A	ENSP00000356224.5
	SYNE1	ENST00000423061.6	TSL:1	c.3526-39A>C		intron	N/A	ENSP00000396024.1
	SYNE1	ENST00000461872.6	TSL:1	n.3723-39A>C		intron	N/A

Frequencies

GnomAD3 genomes AF: 0.520 AC: 79025 AN: 151992 Hom.: 22143 Cov.: 33

Gnomad AFR AF: 0.720

Gnomad AMI AF: 0.285

Gnomad AMR AF: 0.419

Gnomad ASJ AF: 0.497

Gnomad EAS AF: 0.761

Gnomad SAS AF: 0.544

Gnomad FIN AF: 0.392

Gnomad MID AF: 0.525

Gnomad NFE AF: 0.425

Gnomad OTH AF: 0.527

GnomAD2 exomes AF: 0.472 AC: 118444 AN: 250844 AF XY: 0.474

Gnomad AFR exome AF: 0.725

Gnomad AMR exome AF: 0.329

Gnomad ASJ exome AF: 0.489

Gnomad EAS exome AF: 0.765

Gnomad FIN exome AF: 0.406

Gnomad NFE exome AF: 0.430

Gnomad OTH exome AF: 0.450

GnomAD4 exome AF: 0.441 AC: 644357 AN: 1460144 Hom.: 147792 Cov.: 33 AF XY: 0.444 AC XY: 322677 AN XY: 726438

African (AFR) AF: 0.725 AC: 24263 AN: 33458

American (AMR) AF: 0.341 AC: 15262 AN: 44716

Ashkenazi Jewish (ASJ) AF: 0.486 AC: 12708 AN: 26130

East Asian (EAS) AF: 0.789 AC: 31304 AN: 39692

South Asian (SAS) AF: 0.526 AC: 45307 AN: 86190

European-Finnish (FIN) AF: 0.402 AC: 21299 AN: 52998

Middle Eastern (MID) AF: 0.513 AC: 2956 AN: 5766

European-Non Finnish (NFE) AF: 0.417 AC: 462744 AN: 1110842

Other (OTH) AF: 0.472 AC: 28514 AN: 60352

GnomAD4 genome AF: 0.520 AC: 79120 AN: 152112 Hom.: 22183 Cov.: 33 AF XY: 0.518 AC XY: 38549 AN XY: 74374

African (AFR) AF: 0.720 AC: 29878 AN: 41484

American (AMR) AF: 0.419 AC: 6399 AN: 15274

Ashkenazi Jewish (ASJ) AF: 0.497 AC: 1723 AN: 3470

East Asian (EAS) AF: 0.761 AC: 3942 AN: 5178

South Asian (SAS) AF: 0.544 AC: 2630 AN: 4832

European-Finnish (FIN) AF: 0.392 AC: 4149 AN: 10594

Middle Eastern (MID) AF: 0.514 AC: 151 AN: 294

European-Non Finnish (NFE) AF: 0.425 AC: 28877 AN: 67962

Other (OTH) AF: 0.526 AC: 1111 AN: 2112

Alfa AF: 0.467 Hom.: 8467

Bravo AF: 0.530

Asia WGS AF: 0.628 AC: 2184 AN: 3478

ClinVar

ClinVar submissions as Germline

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	1	Arthrogryposis multiplex congenita 3, myogenic type (1)
-	-	1	Autosomal recessive ataxia, Beauce type (1)
-	-	1	Emery-Dreifuss muscular dystrophy 4, autosomal dominant (1)
-	-	1	not provided (1)
-	-	1	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.77
CADD	Benign	0.51
DANN	Benign	0.76
PhyloP100		-0.46
Mutation Taster		=100/0	polymorphism (auto)

Splicing

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

Other links and lift over

dbSNP: rs502268; hg19: chr6-152768796;