2-151633944-A-G

Position:

• chr2-151633944-A-G

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_001164507.2(NEB):​c.9124T>C​(p.Cys3042Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.996 in 1,613,354 control chromosomes in the GnomAD database, including 800,307 homozygotes. In-silico tool predicts a benign outcome for this variant. 11/16 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. C3042H) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.98 (72814 hom., cov: 31)
  • Exomes 𝑓: 1.0 (727493 hom.)
• Consequence: NEB NM_001164507.2 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:9
• Conservation: PhyloP100: 2.10

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=8.425502E-7).
• BP6: Variant 2-151633944-A-G is Benign according to our data. Variant chr2-151633944-A-G is described in ClinVar as [Benign]. Clinvar id is 226847.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr2-151633944-A-G is described in Lovd as [Benign].
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.994 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
NEB	NM_001164507.2	c.9124T>C	p.Cys3042Arg	missense_variant	65/182	ENST00000427231.7
NEB	NM_001164508.2	c.9124T>C	p.Cys3042Arg	missense_variant	65/182	ENST00000397345.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
NEB	ENST00000397345.8	c.9124T>C	p.Cys3042Arg	missense_variant	65/182	5	NM_001164508.2	P5
NEB	ENST00000427231.7	c.9124T>C	p.Cys3042Arg	missense_variant	65/182	5	NM_001164507.2	A2
NEB	ENST00000409198.5	c.8854-2766T>C		intron_variant		5

Frequencies

GnomAD3 genomes AF: 0.977 AC: 148679 AN: 152164 Hom.: 72757 Cov.: 31

Gnomad AFR AF: 0.920

Gnomad AMI AF: 1.00

Gnomad AMR AF: 0.992

Gnomad ASJ AF: 1.00

Gnomad EAS AF: 1.00

Gnomad SAS AF: 1.00

Gnomad FIN AF: 0.999

Gnomad MID AF: 1.00

Gnomad NFE AF: 1.00

Gnomad OTH AF: 0.989

GnomAD3 exomes AF: 0.994 AC: 247644 AN: 249042 Hom.: 123170 AF XY: 0.996 AC XY: 134494 AN XY: 135082

Gnomad AFR exome AF: 0.920

Gnomad AMR exome AF: 0.997

Gnomad ASJ exome AF: 1.00

Gnomad EAS exome AF: 1.00

Gnomad SAS exome AF: 1.00

Gnomad FIN exome AF: 1.00

Gnomad NFE exome AF: 1.00

Gnomad OTH exome AF: 0.998

GnomAD4 exome AF: 0.998 AC: 1457917 AN: 1461072 Hom.: 727493 Cov.: 70 AF XY: 0.998 AC XY: 725414 AN XY: 726706

Gnomad4 AFR exome AF: 0.922

Gnomad4 AMR exome AF: 0.996

Gnomad4 ASJ exome AF: 1.00

Gnomad4 EAS exome AF: 1.00

Gnomad4 SAS exome AF: 1.00

Gnomad4 FIN exome AF: 1.00

Gnomad4 NFE exome AF: 1.00

Gnomad4 OTH exome AF: 0.996

GnomAD4 genome AF: 0.977 AC: 148796 AN: 152282 Hom.: 72814 Cov.: 31 AF XY: 0.978 AC XY: 72830 AN XY: 74458

Gnomad4 AFR AF: 0.920

Gnomad4 AMR AF: 0.992

Gnomad4 ASJ AF: 1.00

Gnomad4 EAS AF: 1.00

Gnomad4 SAS AF: 1.00

Gnomad4 FIN AF: 0.999

Gnomad4 NFE AF: 1.00

Gnomad4 OTH AF: 0.990

Alfa AF: 0.997 Hom.: 92333

Bravo AF: 0.974

TwinsUK AF: 1.00 AC: 3708

ALSPAC AF: 1.00 AC: 3854

ESP6500AA AF: 0.922 AC: 1276

ESP6500EA AF: 0.999 AC: 3179

ExAC AF: 0.993 AC: 119921

Asia WGS AF: 0.997 AC: 3468 AN: 3478

EpiCase AF: 1.00

EpiControl AF: 1.00

ClinVar

Significance: Benign

Submissions summary: Benign:9

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:3

Benign, criteria provided, single submitter	clinical testing	GeneDx	Jan 05, 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, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Dec 10, 2014	This is a RefSeq error. The reference base (c.9124T) is the minor allele. This a llele (T) has been identified in 7.8% (108/1384) of African American chromosomes by the NHLBI Exome Sequencing Project (http://evs.gs.washington.edu/EVS/; dbSNP rs6710212) and thus meets criteria to be classified as benign. -
Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -

Nemaline myopathy 2 Benign:3

Benign, criteria provided, single submitter	clinical testing	Invitae	Feb 01, 2024	- -
Benign, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Jul 10, 2021	- -
Benign, no assertion criteria provided	clinical testing	Natera, Inc.	Sep 16, 2020	- -

not provided Benign:2

Benign, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Feb 27, 2017	Variant summary: The NEB c.9124T>C (p.Cys3042Arg) variant involves the alteration of a non-conserved nucleotide. 3/4 in silico tools predict a benign outcome for this variant. This variant was found in 119893/120760 control chromosomes (59546 homozygotes) at a frequency of 0.9928205, which is approximately 281 times the estimated maximal expected allele frequency of a pathogenic NEB variant (0.0035355), suggesting this variant is the dominant allele. In addition, multiple clinical diagnostic laboratories/reputable databases classified this variant as benign. Taken together, this variant is classified as benign. -
Benign, criteria provided, single submitter	clinical testing	Athena Diagnostics	Mar 04, 2019	- -

Arthrogryposis multiplex congenita 6 Benign:1

Benign, criteria provided, single submitter

clinical testing

Genome-Nilou Lab

Jul 10, 2021

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Benign	-0.64	T
BayesDel_noAF	Benign	-0.63
CADD	Benign	21
DANN	Benign	0.90
DEOGEN2	Benign	0.0033	.;T;.;.;.
Eigen	Benign	-0.59
Eigen_PC	Benign	-0.36
FATHMM_MKL	Benign	0.046	N
LIST_S2	Benign	0.25	T;T;T;.;.
MetaRNN	Benign	8.4e-7	T;T;T;T;T
MetaSVM	Benign	-0.92	T
MutationTaster	Benign	0.055	P;P;P;P
PROVEAN	Benign	3.3	N;.;N;.;.
REVEL	Benign	0.13
Sift	Benign	0.97	T;.;T;.;.
Sift4G	Benign	1.0	T;T;T;T;T
Vest4		0.16
MPC		0.083
ClinPred		0.020	T
GERP RS		6.0
gMVP		0.040

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: rs6710212; hg19: chr2-152490458;