2-151631294-A-T

Position:

• chr2-151631294-A-T

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The NM_001164507.2(NEB):​c.9467T>A​(p.Ile3156Asn) 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 1,613,792 control chromosomes in the GnomAD database, including 261 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.010 (11 hom., cov: 32)
  • Exomes 𝑓: 0.017 (250 hom.)
• Consequence: NEB NM_001164507.2 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:10
• Conservation: PhyloP100: 1.46

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]

ACMG classification

Verdict is Benign. Variant got -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0072318614).
• BP6: Variant 2-151631294-A-T is Benign according to our data. Variant chr2-151631294-A-T is described in ClinVar as [Likely_benign]. Clinvar id is 235444.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr2-151631294-A-T is described in Lovd as [Benign]. Variant chr2-151631294-A-T is described in Lovd as [Likely_benign].
• BS1: Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.0101 (1537/152178) while in subpopulation NFE AF= 0.0176 (1197/67994). AF 95% confidence interval is 0.0168. There are 11 homozygotes in gnomad4. There are 688 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd4 at 11 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
NEB	NM_001164507.2	c.9467T>A	p.Ile3156Asn	missense_variant	66/182	ENST00000427231.7	NP_001157979.2
NEB	NM_001164508.2	c.9467T>A	p.Ile3156Asn	missense_variant	66/182	ENST00000397345.8	NP_001157980.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
NEB	ENST00000397345.8	c.9467T>A	p.Ile3156Asn	missense_variant	66/182	5	NM_001164508.2	ENSP00000380505	P5
NEB	ENST00000427231.7	c.9467T>A	p.Ile3156Asn	missense_variant	66/182	5	NM_001164507.2	ENSP00000416578	A2
NEB	ENST00000409198.5	c.8854-116T>A		intron_variant		5		ENSP00000386259

Frequencies

GnomAD3 genomes AF: 0.0101 AC: 1538 AN: 152060 Hom.: 11 Cov.: 32

Gnomad AFR AF: 0.00345

Gnomad AMI AF: 0.00879

Gnomad AMR AF: 0.00367

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.000193

Gnomad SAS AF: 0.0166

Gnomad FIN AF: 0.00396

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0176

Gnomad OTH AF: 0.00527

GnomAD3 exomes AF: 0.0109 AC: 2716 AN: 249044 Hom.: 26 AF XY: 0.0119 AC XY: 1609 AN XY: 135098

Gnomad AFR exome AF: 0.00323

Gnomad AMR exome AF: 0.00197

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.0211

Gnomad FIN exome AF: 0.00492

Gnomad NFE exome AF: 0.0159

Gnomad OTH exome AF: 0.00844

GnomAD4 exome AF: 0.0166 AC: 24214 AN: 1461614 Hom.: 250 Cov.: 31 AF XY: 0.0165 AC XY: 12024 AN XY: 727078

Gnomad4 AFR exome AF: 0.00269

Gnomad4 AMR exome AF: 0.00219

Gnomad4 ASJ exome AF: 0.000115

Gnomad4 EAS exome AF: 0.000126

Gnomad4 SAS exome AF: 0.0213

Gnomad4 FIN exome AF: 0.00579

Gnomad4 NFE exome AF: 0.0189

Gnomad4 OTH exome AF: 0.0141

GnomAD4 genome AF: 0.0101 AC: 1537 AN: 152178 Hom.: 11 Cov.: 32 AF XY: 0.00924 AC XY: 688 AN XY: 74422

Gnomad4 AFR AF: 0.00344

Gnomad4 AMR AF: 0.00367

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.000193

Gnomad4 SAS AF: 0.0164

Gnomad4 FIN AF: 0.00396

Gnomad4 NFE AF: 0.0176

Gnomad4 OTH AF: 0.00521

Alfa AF: 0.00458 Hom.: 2

Bravo AF: 0.00926

TwinsUK AF: 0.0165 AC: 61

ALSPAC AF: 0.0192 AC: 74

ESP6500AA AF: 0.00289 AC: 4

ESP6500EA AF: 0.0167 AC: 53

ExAC AF: 0.0110 AC: 1325

EpiCase AF: 0.0150

EpiControl AF: 0.0137

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:10

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:5

Benign, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Apr 22, 2019	Variant summary: NEB c.9467T>A (p.Ile3156Asn) results in a non-conservative amino acid change in the encoded protein sequence. One of two in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 0.011 in 280432 control chromosomes, predominantly at a frequency of 0.021 within the South Asian subpopulation in the gnomAD database, including 8 homozygotes. The observed variant frequency within South Asian control individuals in the gnomAD database is approximately 6-folds higher than the estimated maximal expected allele frequency for a pathogenic variant in NEB causing Nemaline Myopathy 2 phenotype (0.0035), strongly suggesting that the variant is a benign polymorphism found primarily in populations of South Asian origin. To our knowledge, no occurrence of c.9467T>A in individuals affected with Nemaline Myopathy 2 and no experimental evidence demonstrating its impact on protein function have been reported. Four ClinVar submissions from clinical diagnostic laboratories (evaluation after 2014) cite the variant as likely benign/benign. Based on the evidence outlined above, the variant was classified as benign. -
Likely benign, criteria provided, single submitter	clinical testing	Athena Diagnostics	May 23, 2017	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Mar 03, 2016	This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease. -
Benign, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, University Medical Center Utrecht	-	- -
Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -

not provided Benign:3

Benign, criteria provided, single submitter	clinical testing	Center for Pediatric Genomic Medicine, Children's Mercy Hospital and Clinics	Dec 21, 2015	- -
Likely benign, no assertion criteria provided	clinical testing	Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC)	-	- -
Likely benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -

Nemaline myopathy 2 Benign:2

Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 31, 2024	- -
Likely benign, no assertion criteria provided	clinical testing	Natera, Inc.	Dec 05, 2019	- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Benign	-0.36	T
BayesDel_noAF	Benign	-0.28
CADD	Benign	21
DANN	Uncertain	0.98
DEOGEN2	Benign	0.084	.;T;.;.;.
Eigen	Benign	0.061
Eigen_PC	Benign	0.087
FATHMM_MKL	Benign	0.49	N
LIST_S2	Uncertain	0.90	D;D;D;.;.
MetaRNN	Benign	0.0072	T;T;T;T;T
MetaSVM	Benign	-1.2	T
MutationTaster	Benign	1.0	D;D;N;N
PROVEAN	Uncertain	-2.6	D;.;D;.;.
REVEL	Benign	0.21
Sift	Benign	0.037	D;.;D;.;.
Sift4G	Pathogenic	0.0010	D;D;D;D;D
Vest4		0.32
MPC		0.41
ClinPred		0.041	T
GERP RS		5.9
gMVP		0.057

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

Publications

LitVar

Other links and lift over

dbSNP: rs145770770; hg19: chr2-152487808;