rs187343008

Variant names:

• chr2-151679785-T-C
• rs187343008
• NM_001164507.2:c.3191A>G

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The NM_001164508.2(NEB):​c.3191A>G​(p.Tyr1064Cys) variant causes a missense change. The variant allele was found at a frequency of 0.00846 in 1,612,676 control chromosomes in the GnomAD database, including 76 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. Y1064N) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.0066 (7 hom., cov: 31)
  • Exomes 𝑓: 0.0087 (69 hom.)
• Consequence: NEB NM_001164508.2 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:12
• Conservation: PhyloP100: 5.07
• Publications: 10 publications found

Genes affected

NEB (HGNC:7720): (nebulin) This gene encodes nebulin, a giant protein component of the cytoskeletal matrix that coexists with the thick and thin filaments within the sarcomeres of skeletal muscle. In most vertebrates, nebulin accounts for 3 to 4% of the total myofibrillar protein. The encoded protein contains approximately 30-amino acid long modules that can be classified into 7 types and other repeated modules. Protein isoform sizes vary from 600 to 800 kD due to alternative splicing that is tissue-, species-,and developmental stage-specific. Of the 183 exons in the nebulin gene, at least 43 are alternatively spliced, although exons 143 and 144 are not found in the same transcript. Of the several thousand transcript variants predicted for nebulin, the RefSeq Project has decided to create three representative RefSeq records. Mutations in this gene are associated with recessive nemaline myopathy. [provided by RefSeq, Sep 2009]

NEB Gene-Disease associations (from GenCC):

• nemaline myopathy 2

  Inheritance: AR, AD Classification: DEFINITIVE, STRONG, LIMITED Submitted by: G2P, Ambry Genetics, Labcorp Genetics (formerly Invitae), Myriad Women’s Health, ClinGen
• autosomal dominant nebulin-related myopathy

  Inheritance: AD Classification: MODERATE Submitted by: ClinGen
• childhood-onset nemaline myopathy

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• intermediate nemaline myopathy

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• typical nemaline myopathy

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• lethal multiple pterygium syndrome

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet
• severe congenital nemaline myopathy

  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=0.013145536).
• BP6: Variant 2-151679785-T-C is Benign according to our data. Variant chr2-151679785-T-C is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 95129.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.00659 (1001/151962) while in subpopulation NFE AF = 0.0107 (728/67940). AF 95% confidence interval is 0.0101. There are 7 homozygotes in GnomAd4. There are 492 alleles in the male GnomAd4 subpopulation. Median coverage is 31. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 7 AD,AR gene

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001164508.2. 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
	NEB	NM_001164507.2	MANE Plus Clinical	c.3191A>G	p.Tyr1064Cys	missense	Exon 32 of 182	NP_001157979.2	P20929-3
	NEB	NM_001164508.2	MANE Select	c.3191A>G	p.Tyr1064Cys	missense	Exon 32 of 182	NP_001157980.2	P20929-2
	NEB	NM_001271208.2		c.3191A>G	p.Tyr1064Cys	missense	Exon 32 of 183	NP_001258137.2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	NEB	ENST00000397345.8	TSL:5 MANE Select	c.3191A>G	p.Tyr1064Cys	missense	Exon 32 of 182	ENSP00000380505.3	P20929-2
	NEB	ENST00000427231.7	TSL:5 MANE Plus Clinical	c.3191A>G	p.Tyr1064Cys	missense	Exon 32 of 182	ENSP00000416578.2	P20929-3
	NEB	ENST00000409198.5	TSL:5	c.3191A>G	p.Tyr1064Cys	missense	Exon 32 of 150	ENSP00000386259.1	P20929-4

Frequencies

GnomAD3 genomes AF: 0.00659 AC: 1001 AN: 151844 Hom.: 7 Cov.: 31

Gnomad AFR AF: 0.00160

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00689

Gnomad ASJ AF: 0.00231

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00104

Gnomad FIN AF: 0.00749

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0107

Gnomad OTH AF: 0.00479

GnomAD2 exomes AF: 0.00649 AC: 1618 AN: 249234 AF XY: 0.00646

Gnomad AFR exome AF: 0.00155

Gnomad AMR exome AF: 0.00298

Gnomad ASJ exome AF: 0.00368

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00808

Gnomad NFE exome AF: 0.0106

Gnomad OTH exome AF: 0.00776

GnomAD4 exome AF: 0.00865 AC: 12639 AN: 1460714 Hom.: 69 Cov.: 33 AF XY: 0.00849 AC XY: 6168 AN XY: 726658

African (AFR) AF: 0.00147 AC: 49 AN: 33430

American (AMR) AF: 0.00280 AC: 125 AN: 44692

Ashkenazi Jewish (ASJ) AF: 0.00356 AC: 93 AN: 26096

East Asian (EAS) AF: 0.0000252 AC: 1 AN: 39642

South Asian (SAS) AF: 0.00136 AC: 117 AN: 86246

European-Finnish (FIN) AF: 0.00773 AC: 412 AN: 53322

Middle Eastern (MID) AF: 0.00139 AC: 8 AN: 5764

European-Non Finnish (NFE) AF: 0.0102 AC: 11376 AN: 1111224

Other (OTH) AF: 0.00760 AC: 458 AN: 60298

GnomAD4 genome AF: 0.00659 AC: 1001 AN: 151962 Hom.: 7 Cov.: 31 AF XY: 0.00662 AC XY: 492 AN XY: 74280

African (AFR) AF: 0.00159 AC: 66 AN: 41492

American (AMR) AF: 0.00688 AC: 105 AN: 15254

Ashkenazi Jewish (ASJ) AF: 0.00231 AC: 8 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5150

South Asian (SAS) AF: 0.00104 AC: 5 AN: 4792

European-Finnish (FIN) AF: 0.00749 AC: 79 AN: 10548

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

European-Non Finnish (NFE) AF: 0.0107 AC: 728 AN: 67940

Other (OTH) AF: 0.00474 AC: 10 AN: 2110

Alfa AF: 0.00940 Hom.: 25

Bravo AF: 0.00576

TwinsUK AF: 0.0129 AC: 48

ALSPAC AF: 0.0101 AC: 39

ESP6500AA AF: 0.00128 AC: 5

ESP6500EA AF: 0.00999 AC: 83

ExAC AF: 0.00654 AC: 791

Asia WGS AF: 0.000577 AC: 2 AN: 3478

EpiCase AF: 0.00943

EpiControl AF: 0.00848

ClinVar

ClinVar submissions

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	5	not specified (5)
-	-	4	not provided (4)
-	-	3	Nemaline myopathy 2 (3)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.15
BayesDel_addAF	Benign	-0.35	T
BayesDel_noAF	Benign	-0.26
CADD	Uncertain	25
DANN	Uncertain	1.0
DEOGEN2	Benign	0.085	T
Eigen	Pathogenic	0.76
Eigen_PC	Pathogenic	0.74
FATHMM_MKL	Uncertain	0.96	D
LIST_S2	Pathogenic	0.98	D
MetaRNN	Benign	0.013	T
MetaSVM	Benign	-1.1	T
MutationAssessor	Uncertain	2.5	M
PhyloP100		5.1
PrimateAI	Uncertain	0.59	T
PROVEAN	Uncertain	-4.2	D
REVEL	Uncertain	0.30
Sift	Benign	0.12	T
Sift4G	Pathogenic	0.0	D
Polyphen		1.0	D
Vest4		0.78
MVP		0.57
MPC		0.37
ClinPred		0.022	T
GERP RS		5.7
Varity_R		0.33
gMVP		0.27
Mutation Taster		=98/2	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.0		Details are displayed if max score is > 0.2

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

Other links and lift over

dbSNP: rs187343008; hg19: chr2-152536299; COSMIC: COSV50809207;