chr6-152219143-A-C

Variant names:

• chr6-152219143-A-C
• rs2147377
• NM_182961.4:c.21904T>G

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.21904T>G​(p.Phe7302Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.99 in 1,614,028 control chromosomes in the GnomAD database, including 790,225 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 (★★). Synonymous variant affecting the same amino acid position (i.e. F7302F) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.99 (74874 hom., cov: 31)
  • Exomes 𝑓: 0.99 (715351 hom.)
• Consequence: SYNE1 NM_182961.4 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:16
• Conservation: PhyloP100: 1.39
• Publications: 28 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: Labcorp Genetics (formerly Invitae), Laboratory for Molecular Medicine, Ambry Genetics, Orphanet, PanelApp Australia, G2P
• Emery-Dreifuss muscular dystrophy 4, autosomal dominant

  Inheritance: AD Classification: STRONG, MODERATE, LIMITED Submitted by: Illumina, Ambry Genetics, PanelApp Australia, Labcorp Genetics (formerly Invitae)
• arthrogryposis multiplex congenita 3, myogenic type

  Inheritance: AR Classification: STRONG, MODERATE Submitted by: PanelApp Australia, Labcorp Genetics (formerly Invitae)
• 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 (MetaRNN=1.3821004E-6).
• BP6: Variant 6-152219143-A-C is Benign according to our data. Variant chr6-152219143-A-C is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 130419.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.989 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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SYNE1	NM_182961.4	MANE Select	c.21904T>G	p.Phe7302Val	missense	Exon 120 of 146	NP_892006.3	Q8NF91-1
	SYNE1	NM_033071.5		c.21691T>G	p.Phe7231Val	missense	Exon 119 of 146	NP_149062.2	Q8NF91-4

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SYNE1	ENST00000367255.10	TSL:1 MANE Select	c.21904T>G	p.Phe7302Val	missense	Exon 120 of 146	ENSP00000356224.5	Q8NF91-1
	SYNE1	ENST00000423061.6	TSL:1	c.21691T>G	p.Phe7231Val	missense	Exon 119 of 146	ENSP00000396024.1	A0A0C4DG40
	SYNE1	ENST00000367251.7	TSL:1	c.670T>G	p.Phe224Val	missense	Exon 5 of 31	ENSP00000356220.3	H0Y325

Frequencies

GnomAD3 genomes AF: 0.992 AC: 150863 AN: 152120 Hom.: 74815 Cov.: 31

Gnomad AFR AF: 0.997

Gnomad AMI AF: 0.953

Gnomad AMR AF: 0.993

Gnomad ASJ AF: 0.995

Gnomad EAS AF: 1.00

Gnomad SAS AF: 0.998

Gnomad FIN AF: 0.989

Gnomad MID AF: 0.997

Gnomad NFE AF: 0.988

Gnomad OTH AF: 0.991

GnomAD2 exomes AF: 0.992 AC: 249278 AN: 251310 AF XY: 0.992

Gnomad AFR exome AF: 0.998

Gnomad AMR exome AF: 0.994

Gnomad ASJ exome AF: 0.994

Gnomad EAS exome AF: 1.00

Gnomad FIN exome AF: 0.988

Gnomad NFE exome AF: 0.988

Gnomad OTH exome AF: 0.991

GnomAD4 exome AF: 0.989 AC: 1446165 AN: 1461790 Hom.: 715351 Cov.: 61 AF XY: 0.989 AC XY: 719528 AN XY: 727212

African (AFR) AF: 0.998 AC: 33424 AN: 33478

American (AMR) AF: 0.994 AC: 44460 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.994 AC: 25983 AN: 26136

East Asian (EAS) AF: 1.00 AC: 39698 AN: 39698

South Asian (SAS) AF: 0.998 AC: 86100 AN: 86256

European-Finnish (FIN) AF: 0.988 AC: 52774 AN: 53414

Middle Eastern (MID) AF: 0.996 AC: 5739 AN: 5764

European-Non Finnish (NFE) AF: 0.988 AC: 1098223 AN: 1111928

Other (OTH) AF: 0.990 AC: 59764 AN: 60392

GnomAD4 genome AF: 0.992 AC: 150981 AN: 152238 Hom.: 74874 Cov.: 31 AF XY: 0.992 AC XY: 73807 AN XY: 74408

African (AFR) AF: 0.997 AC: 41446 AN: 41550

American (AMR) AF: 0.993 AC: 15171 AN: 15284

Ashkenazi Jewish (ASJ) AF: 0.995 AC: 3449 AN: 3466

East Asian (EAS) AF: 1.00 AC: 5161 AN: 5162

South Asian (SAS) AF: 0.998 AC: 4806 AN: 4814

European-Finnish (FIN) AF: 0.989 AC: 10494 AN: 10612

Middle Eastern (MID) AF: 0.997 AC: 293 AN: 294

European-Non Finnish (NFE) AF: 0.988 AC: 67200 AN: 68034

Other (OTH) AF: 0.991 AC: 2094 AN: 2112

Alfa AF: 0.990 Hom.: 219731

Bravo AF: 0.992

TwinsUK AF: 0.987 AC: 3658

ALSPAC AF: 0.988 AC: 3807

ESP6500AA AF: 0.999 AC: 4401

ESP6500EA AF: 0.990 AC: 8515

ExAC AF: 0.992 AC: 120475

Asia WGS AF: 0.999 AC: 3475 AN: 3478

EpiCase AF: 0.988

EpiControl AF: 0.988

ClinVar

ClinVar submissions

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	8	not specified (8)
-	-	2	Autosomal recessive ataxia, Beauce type (2)
-	-	2	Emery-Dreifuss muscular dystrophy 4, autosomal dominant (2)
-	-	2	not provided (2)
-	-	1	Arthrogryposis multiplex congenita 3, myogenic type (1)
-	-	1	Autosomal recessive ataxia, Beauce type;C2751807:Emery-Dreifuss muscular dystrophy 4, autosomal dominant (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.036
BayesDel_addAF	Benign	-0.61	T
BayesDel_noAF	Benign	-0.65
CADD	Benign	13
DANN	Benign	0.21
DEOGEN2	Benign	0.078	T
Eigen	Benign	-1.1
Eigen_PC	Benign	-0.87
FATHMM_MKL	Benign	0.30	N
LIST_S2	Benign	0.044	T
MetaRNN	Benign	0.0000014	T
MetaSVM	Benign	-0.97	T
MutationAssessor	Benign	-2.3	N
PhyloP100		1.4
PrimateAI	Benign	0.40	T
PROVEAN	Benign	2.2	N
REVEL	Benign	0.039
Sift	Benign	1.0	T
Sift4G	Benign	1.0	T
Polyphen		0.0	B
Vest4		0.069
MPC		0.17
ClinPred		0.00072	T
GERP RS		4.0
Varity_R		0.059
gMVP		0.079
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: rs2147377; hg19: chr6-152540278; COSMIC: COSV107318908; COSMIC: COSV107318908;