2-151537930-G-C

Variant names:

• chr2-151537930-G-C
• rs62167164
• NM_001164507.2:c.21044C>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.21044C>G​(p.Ser7015Cys) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0106 in 1,613,300 control chromosomes in the GnomAD database, including 106 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0090 (11 hom., cov: 32)
  • Exomes 𝑓: 0.011 (95 hom.)
• Consequence: NEB NM_001164508.2 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:11
• Conservation: PhyloP100: 9.60
• Publications: 5 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

LOC124906081 (HGNC:):

ACMG classification

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

• BP4: Computational evidence support a benign effect (MetaRNN=0.008066177).
• BP6: Variant 2-151537930-G-C is Benign according to our data. Variant chr2-151537930-G-C is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 129724.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 = 0.00902 (1374/152248) while in subpopulation NFE AF = 0.013 (886/68022). AF 95% confidence interval is 0.0123. There are 11 homozygotes in GnomAd4. There are 704 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 11 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.21044C>G	p.Ser7015Cys	missense	Exon 140 of 182	NP_001157979.2	P20929-3
	NEB	NM_001164508.2	MANE Select	c.21044C>G	p.Ser7015Cys	missense	Exon 140 of 182	NP_001157980.2	P20929-2
	NEB	NM_001271208.2		c.21044C>G	p.Ser7015Cys	missense	Exon 140 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.21044C>G	p.Ser7015Cys	missense	Exon 140 of 182	ENSP00000380505.3	P20929-2
	NEB	ENST00000427231.7	TSL:5 MANE Plus Clinical	c.21044C>G	p.Ser7015Cys	missense	Exon 140 of 182	ENSP00000416578.2	P20929-3
	NEB	ENST00000409198.5	TSL:5	c.15941C>G	p.Ser5314Cys	missense	Exon 113 of 150	ENSP00000386259.1	P20929-4

Frequencies

GnomAD3 genomes AF: 0.00903 AC: 1373 AN: 152130 Hom.: 11 Cov.: 32

Gnomad AFR AF: 0.00183

Gnomad AMI AF: 0.0132

Gnomad AMR AF: 0.00373

Gnomad ASJ AF: 0.00404

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00269

Gnomad FIN AF: 0.0276

Gnomad MID AF: 0.00949

Gnomad NFE AF: 0.0130

Gnomad OTH AF: 0.00956

GnomAD2 exomes AF: 0.00892 AC: 2217 AN: 248626 AF XY: 0.00915

Gnomad AFR exome AF: 0.00162

Gnomad AMR exome AF: 0.00223

Gnomad ASJ exome AF: 0.00707

Gnomad EAS exome AF: 0.0000558

Gnomad FIN exome AF: 0.0234

Gnomad NFE exome AF: 0.0121

Gnomad OTH exome AF: 0.00977

GnomAD4 exome AF: 0.0107 AC: 15671 AN: 1461052 Hom.: 95 Cov.: 30 AF XY: 0.0107 AC XY: 7792 AN XY: 726776

African (AFR) AF: 0.00120 AC: 40 AN: 33458

American (AMR) AF: 0.00226 AC: 101 AN: 44688

Ashkenazi Jewish (ASJ) AF: 0.00716 AC: 187 AN: 26120

East Asian (EAS) AF: 0.00 AC: 0 AN: 39656

South Asian (SAS) AF: 0.00376 AC: 324 AN: 86186

European-Finnish (FIN) AF: 0.0221 AC: 1179 AN: 53388

Middle Eastern (MID) AF: 0.00902 AC: 52 AN: 5762

European-Non Finnish (NFE) AF: 0.0119 AC: 13190 AN: 1111448

Other (OTH) AF: 0.00991 AC: 598 AN: 60346

GnomAD4 genome AF: 0.00902 AC: 1374 AN: 152248 Hom.: 11 Cov.: 32 AF XY: 0.00946 AC XY: 704 AN XY: 74426

African (AFR) AF: 0.00183 AC: 76 AN: 41552

American (AMR) AF: 0.00373 AC: 57 AN: 15290

Ashkenazi Jewish (ASJ) AF: 0.00404 AC: 14 AN: 3468

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

South Asian (SAS) AF: 0.00290 AC: 14 AN: 4828

European-Finnish (FIN) AF: 0.0276 AC: 292 AN: 10588

Middle Eastern (MID) AF: 0.0102 AC: 3 AN: 294

European-Non Finnish (NFE) AF: 0.0130 AC: 886 AN: 68022

Other (OTH) AF: 0.00946 AC: 20 AN: 2114

Alfa AF: 0.0113 Hom.: 10

Bravo AF: 0.00677

TwinsUK AF: 0.0121 AC: 45

ALSPAC AF: 0.0122 AC: 47

ESP6500AA AF: 0.00161 AC: 6

ESP6500EA AF: 0.0118 AC: 97

ExAC AF: 0.00899 AC: 1086

EpiCase AF: 0.0119

EpiControl AF: 0.0120

ClinVar

ClinVar submissions

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

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

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.20
BayesDel_addAF	Benign	-0.24	T
BayesDel_noAF	Benign	-0.10
CADD	Uncertain	25
DANN	Uncertain	0.99
DEOGEN2	Benign	0.054	T
Eigen	Uncertain	0.59
Eigen_PC	Uncertain	0.64
FATHMM_MKL	Pathogenic	0.97	D
LIST_S2	Benign	0.79	T
MetaRNN	Benign	0.0081	T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	0.81	L
PhyloP100		9.6
PrimateAI	Benign	0.46	T
PROVEAN	Uncertain	-2.5	D
REVEL	Benign	0.26
Sift	Benign	0.37	T
Sift4G	Pathogenic	0.0	D
Polyphen		1.0	D
Vest4		0.76
MVP		0.55
MPC		0.34
ClinPred		0.029	T
GERP RS		5.6
Varity_R		0.34
gMVP		0.47
Mutation Taster		=96/4	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: rs62167164; hg19: chr2-152394444; COSMIC: COSV51453522;