2-151633913-C-T

Position:

• chr2-151633913-C-T

Variant summary

Our verdict is Benign. Variant got -13 ACMG points: 0P and 13B. BP4_Strong BP6 BS1 BS2

The NM_001164507.2(NEB):​c.9155G>A​(p.Arg3052Gln) variant causes a missense change. The variant allele was found at a frequency of 0.000416 in 1,613,942 control chromosomes in the GnomAD database, including 4 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R3052W) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.0022 (2 hom., cov: 32)
  • Exomes 𝑓: 0.00023 (2 hom.)
• Consequence: NEB NM_001164507.2 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:3
• Conservation: PhyloP100: 3.84

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 -13 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.008946687).
• BP6: Variant 2-151633913-C-T is Benign according to our data. Variant chr2-151633913-C-T is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 257838.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=3, Uncertain_significance=1}.
• BS1: Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.00219 (333/152260) while in subpopulation AFR AF= 0.00758 (315/41542). AF 95% confidence interval is 0.00689. There are 2 homozygotes in gnomad4. There are 155 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd4 at 2 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
NEB	NM_001164507.2	c.9155G>A	p.Arg3052Gln	missense_variant	65/182	ENST00000427231.7
NEB	NM_001164508.2	c.9155G>A	p.Arg3052Gln	missense_variant	65/182	ENST00000397345.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
NEB	ENST00000397345.8	c.9155G>A	p.Arg3052Gln	missense_variant	65/182	5	NM_001164508.2	P5
NEB	ENST00000427231.7	c.9155G>A	p.Arg3052Gln	missense_variant	65/182	5	NM_001164507.2	A2
NEB	ENST00000409198.5	c.8854-2735G>A		intron_variant		5

Frequencies

GnomAD3 genomes AF: 0.00219 AC: 333 AN: 152142 Hom.: 2 Cov.: 32

Gnomad AFR AF: 0.00761

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000459

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.000386

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.0000943

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000441

Gnomad OTH AF: 0.00239

GnomAD3 exomes AF: 0.000518 AC: 129 AN: 249200 Hom.: 0 AF XY: 0.000414 AC XY: 56 AN XY: 135184

Gnomad AFR exome AF: 0.00723

Gnomad AMR exome AF: 0.000261

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000531

Gnomad OTH exome AF: 0.000331

GnomAD4 exome AF: 0.000231 AC: 338 AN: 1461682 Hom.: 2 Cov.: 114 AF XY: 0.000205 AC XY: 149 AN XY: 727122

Gnomad4 AFR exome AF: 0.00792

Gnomad4 AMR exome AF: 0.000335

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000580

Gnomad4 FIN exome AF: 0.0000187

Gnomad4 NFE exome AF: 0.0000261

Gnomad4 OTH exome AF: 0.000348

GnomAD4 genome AF: 0.00219 AC: 333 AN: 152260 Hom.: 2 Cov.: 32 AF XY: 0.00208 AC XY: 155 AN XY: 74450

Gnomad4 AFR AF: 0.00758

Gnomad4 AMR AF: 0.000458

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.000387

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.0000943

Gnomad4 NFE AF: 0.0000441

Gnomad4 OTH AF: 0.00236

Alfa AF: 0.000242 Hom.: 0

Bravo AF: 0.00270

ESP6500AA AF: 0.00578 AC: 8

ESP6500EA AF: 0.00 AC: 0

ExAC AF: 0.000588 AC: 71

Asia WGS AF: 0.000289 AC: 1 AN: 3478

EpiCase AF: 0.000164

EpiControl AF: 0.00

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1 Benign:3

Revision: criteria provided, conflicting classifications

Submissions by phenotype

Nemaline myopathy 2 Uncertain:1 Benign:1

Likely benign, criteria provided, single submitter	clinical testing	Invitae	Jan 30, 2024	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Baylor Genetics	Oct 24, 2018	This variant was determined to be of uncertain significance according to ACMG Guidelines, 2015 [PMID:25741868]. -

not specified Benign:1

Likely benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

-

- -

not provided Benign:1

Likely benign, criteria provided, single submitter

clinical testing

GeneDx

Apr 07, 2021

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Benign	-0.38	T
BayesDel_noAF	Benign	-0.31
CADD	Benign	23
DANN	Uncertain	1.0
Eigen	Uncertain	0.23
Eigen_PC	Uncertain	0.22
FATHMM_MKL	Uncertain	0.90	D
LIST_S2	Uncertain	0.91	D;D;D;.;.
M_CAP	Benign	0.039	D
MetaRNN	Benign	0.0089	T;T;T;T;T
MetaSVM	Benign	-1.2	T
MutationTaster	Benign	1.0	D;D;N;N
PROVEAN	Benign	-1.4	N;.;N;.;.
REVEL	Benign	0.14
Sift	Uncertain	0.011	D;.;D;.;.
Sift4G	Benign	0.16	T;T;T;T;T
Vest4		0.62
MVP		0.49
MPC		0.27
ClinPred		0.057	T
GERP RS		6.0
gMVP		0.018

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: rs201176993; hg19: chr2-152490427;