rs371605774

Positions:

• chr2-151621016-C-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.10463G>A​(p.Arg3488His) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0014 in 1,607,810 control chromosomes in the GnomAD database, including 44 homozygotes. In-silico tool predicts 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. R3488C) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.00087 (1 hom., cov: 32)
  • Exomes 𝑓: 0.0015 (43 hom.)
• Consequence: NEB NM_001164507.2 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:6
• Conservation: PhyloP100: 0.501

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=0.0062686205).
• BP6: Variant 2-151621016-C-T is Benign according to our data. Variant chr2-151621016-C-T is described in ClinVar as [Benign]. Clinvar id is 198375.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr2-151621016-C-T is described in Lovd as [Likely_benign].
• BS1: Variant frequency is greater than expected in population sas. gnomad4 allele frequency = 0.000867 (132/152240) while in subpopulation SAS AF= 0.026 (125/4812). AF 95% confidence interval is 0.0223. There are 1 homozygotes in gnomad4. There are 94 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.
• BS2: High Homozygotes in GnomAdExome4 at 43 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
NEB	NM_001164507.2	c.10463G>A	p.Arg3488His	missense_variant	72/182	ENST00000427231.7
NEB	NM_001164508.2	c.10463G>A	p.Arg3488His	missense_variant	72/182	ENST00000397345.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
NEB	ENST00000397345.8	c.10463G>A	p.Arg3488His	missense_variant	72/182	5	NM_001164508.2	P5
NEB	ENST00000427231.7	c.10463G>A	p.Arg3488His	missense_variant	72/182	5	NM_001164507.2	A2
NEB	ENST00000409198.5	c.9734G>A	p.Arg3245His	missense_variant	69/150	5

Frequencies

GnomAD3 genomes AF: 0.000868 AC: 132 AN: 152122 Hom.: 1 Cov.: 32

Gnomad AFR AF: 0.0000724

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0000655

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.0260

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000294

Gnomad OTH AF: 0.000478

GnomAD3 exomes AF: 0.00289 AC: 690 AN: 238534 Hom.: 11 AF XY: 0.00382 AC XY: 493 AN XY: 129102

Gnomad AFR exome AF: 0.000137

Gnomad AMR exome AF: 0.0000299

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.000173

Gnomad SAS exome AF: 0.0230

Gnomad FIN exome AF: 0.0000474

Gnomad NFE exome AF: 0.0000373

Gnomad OTH exome AF: 0.00188

GnomAD4 exome AF: 0.00146 AC: 2119 AN: 1455570 Hom.: 43 Cov.: 30 AF XY: 0.00207 AC XY: 1501 AN XY: 723462

Gnomad4 AFR exome AF: 0.000180

Gnomad4 AMR exome AF: 0.0000454

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.0000759

Gnomad4 SAS exome AF: 0.0233

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000244

Gnomad4 OTH exome AF: 0.00153

GnomAD4 genome AF: 0.000867 AC: 132 AN: 152240 Hom.: 1 Cov.: 32 AF XY: 0.00126 AC XY: 94 AN XY: 74424

Gnomad4 AFR AF: 0.0000722

Gnomad4 AMR AF: 0.0000654

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.0260

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000294

Gnomad4 OTH AF: 0.000473

Alfa AF: 0.000242 Hom.: 0

Bravo AF: 0.000200

TwinsUK AF: 0.000539 AC: 2

ALSPAC AF: 0.000259 AC: 1

ExAC AF: 0.00331 AC: 400

Asia WGS AF: 0.0110 AC: 39 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:6

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:3

Benign, criteria provided, single submitter	clinical testing	GeneDx	Jul 31, 2017	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, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Apr 15, 2015	- -
Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -

Nemaline myopathy 2 Benign:3

Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 31, 2024	- -
Benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Jan 12, 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 benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -
Benign, no assertion criteria provided	clinical testing	Natera, Inc.	Sep 16, 2020	- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.12
BayesDel_addAF	Benign	-0.37	T
BayesDel_noAF	Benign	-0.28
CADD	Uncertain	25
DANN	Pathogenic	1.0
DEOGEN2	Benign	0.042	.;.;T;.;T;.;.
Eigen	Uncertain	0.50
Eigen_PC	Uncertain	0.51
FATHMM_MKL	Benign	0.32	N
LIST_S2	Benign	0.83	T;D;D;D;T;.;.
MetaRNN	Benign	0.0063	T;T;T;T;T;T;T
MetaSVM	Benign	-0.72	T
MutationAssessor	Uncertain	2.3	M;.;.;.;M;.;.
MutationTaster	Benign	1.0	N;N;N;N
PrimateAI	Benign	0.43	T
PROVEAN	Benign	-1.6	N;N;.;N;N;.;.
REVEL	Benign	0.23
Sift	Uncertain	0.026	D;D;.;D;D;.;.
Sift4G	Uncertain	0.020	D;D;D;D;D;D;D
Polyphen		1.0	.;.;.;.;D;.;.
Vest4		0.21
MVP		0.64
MPC		0.33
ClinPred		0.041	T
GERP RS		5.7
Varity_R		0.10
gMVP		0.24

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: rs371605774; hg19: chr2-152477530; COSMIC: COSV51443222; COSMIC: COSV51443222;