rs36105240

Positions:

• chr2-151710447-T-C

Variant summary

Our verdict is Benign. Variant got -15 ACMG points: 1P and 16B. PP3 BP6_Very_Strong BS1 BS2

The NM_001164507.2(NEB):​c.914A>G​(p.Asp305Gly) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00171 in 1,611,260 control chromosomes in the GnomAD database, including 39 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0019 (4 hom., cov: 32)
  • Exomes 𝑓: 0.0017 (35 hom.)
• Consequence: NEB NM_001164507.2 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:10
• Conservation: PhyloP100: 2.75

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 -15 ACMG points.

• PP3: Splicing scoreres supports a deletorius effect: Scorers claiming Pathogenic: max_spliceai. No scorers claiming Uncertain. No scorers claiming Benign.
• BP6: Variant 2-151710447-T-C is Benign according to our data. Variant chr2-151710447-T-C is described in ClinVar as [Likely_benign]. Clinvar id is 193880.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population eas. gnomad4 allele frequency = 0.00188 (286/152314) while in subpopulation EAS AF= 0.0232 (120/5178). AF 95% confidence interval is 0.0198. There are 4 homozygotes in gnomad4. There are 175 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd4 at 4 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
NEB	NM_001164507.2	c.914A>G	p.Asp305Gly	missense_variant	11/182	ENST00000427231.7	NP_001157979.2
NEB	NM_001164508.2	c.914A>G	p.Asp305Gly	missense_variant	11/182	ENST00000397345.8	NP_001157980.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
NEB	ENST00000397345.8	c.914A>G	p.Asp305Gly	missense_variant	11/182	5	NM_001164508.2	ENSP00000380505	P5
NEB	ENST00000427231.7	c.914A>G	p.Asp305Gly	missense_variant	11/182	5	NM_001164507.2	ENSP00000416578	A2
NEB	ENST00000409198.5	c.914A>G	p.Asp305Gly	missense_variant	11/150	5		ENSP00000386259

Frequencies

GnomAD3 genomes AF: 0.00188 AC: 286 AN: 152196 Hom.: 4 Cov.: 32

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.000577

Gnomad EAS AF: 0.0231

Gnomad SAS AF: 0.00104

Gnomad FIN AF: 0.0108

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000617

Gnomad OTH AF: 0.000956

GnomAD3 exomes AF: 0.00321 AC: 798 AN: 248910 Hom.: 8 AF XY: 0.00294 AC XY: 397 AN XY: 135020

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00199

Gnomad EAS exome AF: 0.0191

Gnomad SAS exome AF: 0.000294

Gnomad FIN exome AF: 0.0113

Gnomad NFE exome AF: 0.00147

Gnomad OTH exome AF: 0.00298

GnomAD4 exome AF: 0.00170 AC: 2474 AN: 1458946 Hom.: 35 Cov.: 29 AF XY: 0.00165 AC XY: 1196 AN XY: 725936

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.0000447

Gnomad4 ASJ exome AF: 0.00234

Gnomad4 EAS exome AF: 0.0338

Gnomad4 SAS exome AF: 0.000349

Gnomad4 FIN exome AF: 0.0108

Gnomad4 NFE exome AF: 0.000297

Gnomad4 OTH exome AF: 0.00219

GnomAD4 genome AF: 0.00188 AC: 286 AN: 152314 Hom.: 4 Cov.: 32 AF XY: 0.00235 AC XY: 175 AN XY: 74488

Gnomad4 AFR AF: 0.00

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.000577

Gnomad4 EAS AF: 0.0232

Gnomad4 SAS AF: 0.00104

Gnomad4 FIN AF: 0.0108

Gnomad4 NFE AF: 0.000617

Gnomad4 OTH AF: 0.000946

Alfa AF: 0.000929 Hom.: 3

Bravo AF: 0.00100

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.000362 AC: 3

ExAC AF: 0.00348 AC: 421

Asia WGS AF: 0.0100 AC: 37 AN: 3478

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:10

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Nemaline myopathy 2 Benign:5

Benign, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Jun 10, 2021	- -
Likely benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Jan 13, 2018	This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as likely benign is not then subjected to further curation. The score for this variant resulted in a classification of likely benign for this disease. -
Benign, no assertion criteria provided	clinical testing	Natera, Inc.	Jan 07, 2020	- -
Likely benign, criteria provided, single submitter	clinical testing	Counsyl	May 24, 2018	- -
Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 31, 2024	- -

not specified Benign:2

Benign, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Feb 24, 2022	Variant summary: NEB c.914A>G (p.Asp305Gly) results in a non-conservative amino acid change in the encoded protein sequence. Four of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 0.0032 in 248910 control chromosomes, predominantly at a frequency of 0.019 within the East Asian subpopulation in the gnomAD database, including 6 homozygotes. The observed variant frequency within East Asian control individuals in the gnomAD database is approximately 5.4 fold of 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 East Asian origin. To our knowledge, no occurrence of c.914A>G in individuals affected with Nemaline Myopathy 2 and no experimental evidence demonstrating its impact on protein function have been reported. Six clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. All laboratories classified the variant as benign/likely benign. Based on the evidence outlined above, the variant was classified as benign. -
Benign, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Nov 20, 2014	- -

not provided Benign:2

Benign, criteria provided, single submitter	clinical testing	GeneDx	Jun 25, 2020	This variant is associated with the following publications: (PMID: 28391287) -
Likely benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -

Nemaline myopathy 2;C5543431:Arthrogryposis multiplex congenita 6 Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Fulgent Genetics, Fulgent Genetics

Nov 05, 2021

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.11
BayesDel_addAF	Benign	-0.60	T
BayesDel_noAF	Benign	-0.61
CADD	Uncertain	23
DANN	Benign	0.92
DEOGEN2	Benign	0.060	.;.;T;.;T;.;.
Eigen	Benign	-0.51
Eigen_PC	Benign	-0.39
FATHMM_MKL	Benign	0.71	D
LIST_S2	Uncertain	0.89	D;D;D;D;D;.;.
MetaRNN	Benign	0.0076	T;T;T;T;T;T;T
MetaSVM	Benign	-0.93	T
MutationAssessor	Benign	1.4	L;L;.;L;L;L;L
MutationTaster	Benign	0.92	N;N;N;N
PrimateAI	Benign	0.30	T
PROVEAN	Benign	-2.2	N;D;.;D;N;.;.
REVEL	Benign	0.078
Sift	Benign	0.20	T;T;.;T;T;.;.
Sift4G	Uncertain	0.0040	D;D;D;D;D;D;D
Polyphen		0.032	.;.;.;.;B;.;.
Vest4		0.46
MVP		0.34
MPC		0.14
ClinPred		0.038	T
GERP RS		4.5
Varity_R		0.16
gMVP		0.49

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.75		Details are displayed if max score is > 0.2
DS_DG_spliceai		0.75		Position offset: 1

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

Publications

LitVar

Other links and lift over

dbSNP: rs36105240; hg19: chr2-152566961;