rs373946448

Positions:

• chr2-151690754-G-A

Variant summary

Our verdict is Benign. Variant got -8 ACMG points: 2P and 10B. PM2 BP4_Strong BP6 BP7 BS1

The NM_001164507.2(NEB):​c.2283C>T​(p.Ala761=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000183 in 1,597,424 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.00099 (0 hom., cov: 32)
  • Exomes 𝑓: 0.000099 (0 hom.)
• Consequence: NEB NM_001164507.2 synonymous
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:2 B:2
• Conservation: PhyloP100: 0.454

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 -8 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.52).
• BP6: Variant 2-151690754-G-A is Benign according to our data. Variant chr2-151690754-G-A is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 195822.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=1, Uncertain_significance=1, Benign=1}.
• BP7: Synonymous conserved (PhyloP=0.454 with no splicing effect.
• BS1: Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.000985 (150/152236) while in subpopulation AFR AF= 0.0034 (141/41528). AF 95% confidence interval is 0.00294. There are 0 homozygotes in gnomad4. There are 74 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
NEB	NM_001164507.2	c.2283C>T	p.Ala761=	synonymous_variant	24/182	ENST00000427231.7
NEB	NM_001164508.2	c.2283C>T	p.Ala761=	synonymous_variant	24/182	ENST00000397345.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
NEB	ENST00000397345.8	c.2283C>T	p.Ala761=	synonymous_variant	24/182	5	NM_001164508.2	P5
NEB	ENST00000427231.7	c.2283C>T	p.Ala761=	synonymous_variant	24/182	5	NM_001164507.2	A2
NEB	ENST00000489048.1	n.1182C>T		non_coding_transcript_exon_variant	12/12	1
NEB	ENST00000409198.5	c.2283C>T	p.Ala761=	synonymous_variant	24/150	5

Frequencies

GnomAD3 genomes AF: 0.000986 AC: 150 AN: 152118 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.00341

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000327

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.00191

GnomAD3 exomes AF: 0.000226 AC: 51 AN: 225518 Hom.: 0 AF XY: 0.000190 AC XY: 23 AN XY: 120846

Gnomad AFR exome AF: 0.00345

Gnomad AMR exome AF: 0.0000627

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: 0.00

Gnomad OTH exome AF: 0.000179

GnomAD4 exome AF: 0.0000989 AC: 143 AN: 1445188 Hom.: 0 Cov.: 30 AF XY: 0.0000921 AC XY: 66 AN XY: 716744

Gnomad4 AFR exome AF: 0.00367

Gnomad4 AMR exome AF: 0.0000707

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00

Gnomad4 OTH exome AF: 0.000284

GnomAD4 genome AF: 0.000985 AC: 150 AN: 152236 Hom.: 0 Cov.: 32 AF XY: 0.000994 AC XY: 74 AN XY: 74432

Gnomad4 AFR AF: 0.00340

Gnomad4 AMR AF: 0.000327

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.00

Gnomad4 OTH AF: 0.00189

Alfa AF: 0.000576 Hom.: 0

Bravo AF: 0.00110

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:2 Benign:2

Revision: criteria provided, conflicting classifications

Submissions by phenotype

Nemaline myopathy 2 Uncertain:1 Benign:1

Uncertain significance, no assertion criteria provided	clinical testing	Natera, Inc.	Jan 24, 2020	- -
Benign, criteria provided, single submitter	clinical testing	Invitae	Jan 24, 2024	- -

not provided Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Eurofins Ntd Llc (ga)

Sep 12, 2014

- -

not specified Benign:1

Likely benign, criteria provided, single submitter

clinical testing

GeneDx

Dec 26, 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. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.52
CADD	Benign	4.7
DANN	Benign	0.63

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: rs373946448; hg19: chr2-152547268;