6-152390293-C-T

Variant names:

• chr6-152390293-C-T
• rs151091241
• NM_182961.4:c.8164G>A

Variant summary

Our verdict is Benign. The variant received -16 ACMG points: 0P and 16B. BP4_Strong BP6_Very_Strong BS2

The NM_182961.4(SYNE1):​c.8164G>A​(p.Val2722Ile) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00741 in 1,613,912 control chromosomes in the GnomAD database, including 60 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0067 (2 hom., cov: 32)
  • Exomes 𝑓: 0.0075 (58 hom.)
• Consequence: SYNE1 NM_182961.4 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:12
• Conservation: PhyloP100: -0.705
• Publications: 14 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 -16 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0038227737).
• BP6: Variant 6-152390293-C-T is Benign according to our data. Variant chr6-152390293-C-T is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 197955.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS2: High Homozygotes in GnomAd4 at 2 AR,AD gene

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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SYNE1	NM_182961.4	MANE Select	c.8164G>A	p.Val2722Ile	missense	Exon 53 of 146	NP_892006.3
	SYNE1	NM_033071.5		c.8185G>A	p.Val2729Ile	missense	Exon 53 of 146	NP_149062.2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SYNE1	ENST00000367255.10	TSL:1 MANE Select	c.8164G>A	p.Val2722Ile	missense	Exon 53 of 146	ENSP00000356224.5
	SYNE1	ENST00000423061.6	TSL:1	c.8185G>A	p.Val2729Ile	missense	Exon 53 of 146	ENSP00000396024.1
	SYNE1	ENST00000461872.6	TSL:1	n.8382G>A		non_coding_transcript_exon	Exon 51 of 55

Frequencies

GnomAD3 genomes AF: 0.00669 AC: 1018 AN: 152088 Hom.: 2 Cov.: 32

Gnomad AFR AF: 0.00186

Gnomad AMI AF: 0.0285

Gnomad AMR AF: 0.00400

Gnomad ASJ AF: 0.0127

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00310

Gnomad FIN AF: 0.0116

Gnomad MID AF: 0.00316

Gnomad NFE AF: 0.00969

Gnomad OTH AF: 0.00574

GnomAD2 exomes AF: 0.00607 AC: 1524 AN: 251248 AF XY: 0.00627

Gnomad AFR exome AF: 0.00123

Gnomad AMR exome AF: 0.00159

Gnomad ASJ exome AF: 0.0103

Gnomad EAS exome AF: 0.000163

Gnomad FIN exome AF: 0.0111

Gnomad NFE exome AF: 0.00847

Gnomad OTH exome AF: 0.00457

GnomAD4 exome AF: 0.00749 AC: 10946 AN: 1461708 Hom.: 58 Cov.: 33 AF XY: 0.00756 AC XY: 5500 AN XY: 727146

African (AFR) AF: 0.00122 AC: 41 AN: 33476

American (AMR) AF: 0.00174 AC: 78 AN: 44716

Ashkenazi Jewish (ASJ) AF: 0.0111 AC: 290 AN: 26130

East Asian (EAS) AF: 0.000176 AC: 7 AN: 39692

South Asian (SAS) AF: 0.00393 AC: 339 AN: 86246

European-Finnish (FIN) AF: 0.0104 AC: 554 AN: 53412

Middle Eastern (MID) AF: 0.00627 AC: 36 AN: 5742

European-Non Finnish (NFE) AF: 0.00829 AC: 9213 AN: 1111916

Other (OTH) AF: 0.00643 AC: 388 AN: 60378

GnomAD4 genome AF: 0.00669 AC: 1018 AN: 152204 Hom.: 2 Cov.: 32 AF XY: 0.00642 AC XY: 478 AN XY: 74432

African (AFR) AF: 0.00185 AC: 77 AN: 41532

American (AMR) AF: 0.00399 AC: 61 AN: 15280

Ashkenazi Jewish (ASJ) AF: 0.0127 AC: 44 AN: 3464

East Asian (EAS) AF: 0.00 AC: 0 AN: 5180

South Asian (SAS) AF: 0.00311 AC: 15 AN: 4830

European-Finnish (FIN) AF: 0.0116 AC: 123 AN: 10602

Middle Eastern (MID) AF: 0.00340 AC: 1 AN: 294

European-Non Finnish (NFE) AF: 0.00969 AC: 659 AN: 67998

Other (OTH) AF: 0.00568 AC: 12 AN: 2112

Alfa AF: 0.00794 Hom.: 12

Bravo AF: 0.00599

TwinsUK AF: 0.00917 AC: 34

ALSPAC AF: 0.00804 AC: 31

ESP6500AA AF: 0.00204 AC: 9

ESP6500EA AF: 0.00977 AC: 84

ExAC AF: 0.00632 AC: 767

Asia WGS AF: 0.00115 AC: 4 AN: 3478

EpiCase AF: 0.00807

EpiControl AF: 0.00782

ClinVar

ClinVar submissions as Germline

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	4	not provided (4)
-	-	4	not specified (4)
-	-	1	Autosomal recessive ataxia, Beauce type (1)
-	-	1	Autosomal recessive ataxia, Beauce type;C2751807:Emery-Dreifuss muscular dystrophy 4, autosomal dominant (1)
-	-	1	Emery-Dreifuss muscular dystrophy 4, autosomal dominant (1)
-	-	1	SYNE1-related disorder (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.066
BayesDel_addAF	Benign	-0.68	T
BayesDel_noAF	Benign	-0.74
CADD	Benign	0.0080
DANN	Benign	0.69
DEOGEN2	Benign	0.12	T
Eigen	Benign	-1.6
Eigen_PC	Benign	-1.7
FATHMM_MKL	Benign	0.019	N
LIST_S2	Benign	0.27	T
MetaRNN	Benign	0.0038	T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	0.97	L
PhyloP100		-0.70
PrimateAI	Benign	0.23	T
PROVEAN	Benign	0.090	N
REVEL	Benign	0.039
Sift	Benign	0.53	T
Sift4G	Benign	0.14	T
Polyphen		0.0010	B
Vest4		0.12
MVP		0.085
MPC		0.11
ClinPred		0.0026	T
GERP RS		-12
Varity_R		0.018
gMVP		0.024
Mutation Taster		=95/5	polymorphism

Splicing

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

Other links and lift over

dbSNP: rs151091241; hg19: chr6-152711428; COSMIC: COSV54953187;