chr6-152347076-A-G

Variant names:

• chr6-152347076-A-G
• rs111449472
• NM_182961.4:c.12061T>C

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.12061T>C​(p.Cys4021Arg) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0125 in 1,614,208 control chromosomes in the GnomAD database, including 162 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0091 (11 hom., cov: 32)
  • Exomes 𝑓: 0.013 (151 hom.)
• Consequence: SYNE1 NM_182961.4 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:12
• Conservation: PhyloP100: 8.89
• Publications: 5 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=0.009058833).
• BP6: Variant 6-152347076-A-G is Benign according to our data. Variant chr6-152347076-A-G is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 262155.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS2: High Homozygotes in GnomAd4 at 11 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.12061T>C	p.Cys4021Arg	missense	Exon 73 of 146	NP_892006.3
	SYNE1	NM_033071.5		c.11848T>C	p.Cys3950Arg	missense	Exon 72 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.12061T>C	p.Cys4021Arg	missense	Exon 73 of 146	ENSP00000356224.5
	SYNE1	ENST00000423061.6	TSL:1	c.11848T>C	p.Cys3950Arg	missense	Exon 72 of 146	ENSP00000396024.1
	SYNE1	ENST00000471834.1	TSL:1	n.5199T>C		non_coding_transcript_exon	Exon 16 of 19

Frequencies

GnomAD3 genomes AF: 0.00914 AC: 1392 AN: 152224 Hom.: 11 Cov.: 32

Gnomad AFR AF: 0.00292

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00504

Gnomad ASJ AF: 0.0107

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00518

Gnomad FIN AF: 0.0117

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0146

Gnomad OTH AF: 0.00813

GnomAD2 exomes AF: 0.0102 AC: 2554 AN: 251464 AF XY: 0.0102

Gnomad AFR exome AF: 0.00252

Gnomad AMR exome AF: 0.00387

Gnomad ASJ exome AF: 0.00992

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.0116

Gnomad NFE exome AF: 0.0160

Gnomad OTH exome AF: 0.0122

GnomAD4 exome AF: 0.0128 AC: 18762 AN: 1461866 Hom.: 151 Cov.: 31 AF XY: 0.0125 AC XY: 9066 AN XY: 727234

African (AFR) AF: 0.00188 AC: 63 AN: 33478

American (AMR) AF: 0.00409 AC: 183 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.0104 AC: 273 AN: 26136

East Asian (EAS) AF: 0.0000252 AC: 1 AN: 39700

South Asian (SAS) AF: 0.00478 AC: 412 AN: 86256

European-Finnish (FIN) AF: 0.0135 AC: 722 AN: 53418

Middle Eastern (MID) AF: 0.00191 AC: 11 AN: 5756

European-Non Finnish (NFE) AF: 0.0148 AC: 16426 AN: 1112004

Other (OTH) AF: 0.0111 AC: 671 AN: 60394

GnomAD4 genome AF: 0.00914 AC: 1392 AN: 152342 Hom.: 11 Cov.: 32 AF XY: 0.00922 AC XY: 687 AN XY: 74498

African (AFR) AF: 0.00291 AC: 121 AN: 41588

American (AMR) AF: 0.00503 AC: 77 AN: 15306

Ashkenazi Jewish (ASJ) AF: 0.0107 AC: 37 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5182

South Asian (SAS) AF: 0.00539 AC: 26 AN: 4820

European-Finnish (FIN) AF: 0.0117 AC: 124 AN: 10624

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.0146 AC: 990 AN: 68032

Other (OTH) AF: 0.00804 AC: 17 AN: 2114

Alfa AF: 0.0127 Hom.: 35

Bravo AF: 0.00829

TwinsUK AF: 0.0113 AC: 42

ALSPAC AF: 0.0176 AC: 68

ESP6500AA AF: 0.00363 AC: 16

ESP6500EA AF: 0.0151 AC: 130

ExAC AF: 0.0113 AC: 1371

Asia WGS AF: 0.00202 AC: 7 AN: 3478

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	Uncertain	0.38
BayesDel_addAF	Benign	-0.37	T
BayesDel_noAF	Benign	-0.29
CADD	Uncertain	25
DANN	Benign	0.96
DEOGEN2	Uncertain	0.67	D
Eigen	Uncertain	0.67
Eigen_PC	Pathogenic	0.70
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.93	D
MetaRNN	Benign	0.0091	T
MetaSVM	Benign	-0.92	T
MutationAssessor	Uncertain	2.0	M
PhyloP100		8.9
PrimateAI	Pathogenic	0.82	D
PROVEAN	Pathogenic	-4.9	D
REVEL	Uncertain	0.31
Sift	Pathogenic	0.0	D
Sift4G	Pathogenic	0.0	D
Polyphen		1.0	D
Vest4		0.32
MPC		0.82
ClinPred		0.026	T
GERP RS		5.7
Varity_R		0.92
gMVP		0.51
Mutation Taster		=33/67	disease causing

Splicing

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

Other links and lift over

dbSNP: rs111449472; hg19: chr6-152668211; COSMIC: COSV99037638;