rs149025191

Variant names:

• chr2-151617397-C-G
• rs149025191
• NM_001164507.2:c.11148G>C

Your query was ambiguous. Multiple possible variants found:

• chr2-151617397-C-G
• chr2-151617397-C-T

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.11148G>C​(p.Met3716Ile) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.016 in 1,564,866 control chromosomes in the GnomAD database, including 269 homozygotes. In-silico tool predicts a benign outcome for this variant. 13/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. M3716T) has been classified as Uncertain significance. The gene NEB is included in the ClinGen Criteria Specification Registry.

• Frequency:
  • Genomes: 𝑓 0.014 (29 hom., cov: 31)
  • Exomes 𝑓: 0.016 (240 hom.)
• Consequence: NEB NM_001164508.2 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:9
• Conservation: PhyloP100: 0.485
• Publications: 7 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

Specifications for NEB are available in the ClinGen Criteria Specification Registry and recommended for reference when assigning criteria.

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

• BP4: Computational evidence support a benign effect (MetaRNN=0.006017059).
• BP6: Variant 2-151617397-C-G is Benign according to our data. Variant chr2-151617397-C-G is described in ClinVar as Benign. ClinVar VariationId is 129706.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 = 0.0136 (2035/149722) while in subpopulation NFE AF = 0.0185 (1257/67786). AF 95% confidence interval is 0.0177. There are 29 homozygotes in GnomAd4. There are 1043 alleles in the male GnomAd4 subpopulation. Median coverage is 31. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 29 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.11148G>C	p.Met3716Ile	missense	Exon 75 of 182	NP_001157979.2	P20929-3
	NEB	NM_001164508.2	MANE Select	c.11148G>C	p.Met3716Ile	missense	Exon 75 of 182	NP_001157980.2	P20929-2
	NEB	NM_001271208.2		c.11148G>C	p.Met3716Ile	missense	Exon 75 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.11148G>C	p.Met3716Ile	missense	Exon 75 of 182	ENSP00000380505.3	P20929-2
	NEB	ENST00000427231.7	TSL:5 MANE Plus Clinical	c.11148G>C	p.Met3716Ile	missense	Exon 75 of 182	ENSP00000416578.2	P20929-3
	NEB	ENST00000409198.5	TSL:5	c.10419G>C	p.Met3473Ile	missense	Exon 72 of 150	ENSP00000386259.1	P20929-4

Frequencies

GnomAD3 genomes AF: 0.0136 AC: 2037 AN: 149610 Hom.: 29 Cov.: 31

Gnomad AFR AF: 0.00302

Gnomad AMI AF: 0.0144

Gnomad AMR AF: 0.0127

Gnomad ASJ AF: 0.00896

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.0149

Gnomad FIN AF: 0.0325

Gnomad MID AF: 0.00641

Gnomad NFE AF: 0.0185

Gnomad OTH AF: 0.0145

GnomAD2 exomes AF: 0.0135 AC: 2609 AN: 192764 AF XY: 0.0143

Gnomad AFR exome AF: 0.00235

Gnomad AMR exome AF: 0.00726

Gnomad ASJ exome AF: 0.0110

Gnomad EAS exome AF: 0.0000679

Gnomad FIN exome AF: 0.0299

Gnomad NFE exome AF: 0.0152

Gnomad OTH exome AF: 0.0161

GnomAD4 exome AF: 0.0162 AC: 22937 AN: 1415144 Hom.: 240 Cov.: 31 AF XY: 0.0162 AC XY: 11347 AN XY: 700108

African (AFR) AF: 0.00254 AC: 83 AN: 32710

American (AMR) AF: 0.00822 AC: 322 AN: 39180

Ashkenazi Jewish (ASJ) AF: 0.0111 AC: 280 AN: 25334

East Asian (EAS) AF: 0.0000262 AC: 1 AN: 38152

South Asian (SAS) AF: 0.0156 AC: 1267 AN: 81076

European-Finnish (FIN) AF: 0.0303 AC: 1507 AN: 49740

Middle Eastern (MID) AF: 0.0102 AC: 58 AN: 5684

European-Non Finnish (NFE) AF: 0.0171 AC: 18563 AN: 1084858

Other (OTH) AF: 0.0147 AC: 856 AN: 58410

GnomAD4 genome AF: 0.0136 AC: 2035 AN: 149722 Hom.: 29 Cov.: 31 AF XY: 0.0143 AC XY: 1043 AN XY: 72936

African (AFR) AF: 0.00301 AC: 122 AN: 40540

American (AMR) AF: 0.0127 AC: 190 AN: 14986

Ashkenazi Jewish (ASJ) AF: 0.00896 AC: 31 AN: 3460

East Asian (EAS) AF: 0.00 AC: 0 AN: 5040

South Asian (SAS) AF: 0.0145 AC: 69 AN: 4758

European-Finnish (FIN) AF: 0.0325 AC: 321 AN: 9862

Middle Eastern (MID) AF: 0.00685 AC: 2 AN: 292

European-Non Finnish (NFE) AF: 0.0185 AC: 1257 AN: 67786

Other (OTH) AF: 0.0143 AC: 30 AN: 2094

Alfa AF: 0.0151 Hom.: 18

Bravo AF: 0.0112

TwinsUK AF: 0.0200 AC: 74

ALSPAC AF: 0.0148 AC: 57

ESP6500AA AF: 0.00346 AC: 13

ESP6500EA AF: 0.0178 AC: 146

ExAC AF: 0.00932 AC: 1106

Asia WGS AF: 0.00751 AC: 26 AN: 3478

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

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

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.26
BayesDel_addAF	Benign	-0.54	T
BayesDel_noAF	Benign	-0.53
CADD	Benign	21
DANN	Uncertain	0.98
DEOGEN2	Benign	0.013	T
Eigen	Benign	-0.54
Eigen_PC	Benign	-0.33
FATHMM_MKL	Benign	0.38	N
LIST_S2	Uncertain	0.87	D
MetaRNN	Benign	0.0060	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	-0.33	N
PhyloP100		0.48
PrimateAI	Uncertain	0.55	T
PROVEAN	Benign	-1.1	N
REVEL	Benign	0.11
Sift	Benign	0.41	T
Sift4G	Uncertain	0.049	D
Polyphen		0.060	B
Vest4		0.39
MutPred		0.52		Loss of ubiquitination at K3476 (P = 0.0957)
MPC		0.061
ClinPred		0.018	T
GERP RS		5.2
Varity_R		0.23
gMVP		0.11
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: rs149025191; hg19: chr2-152473911; COSMIC: COSV50807099;