rs369897667

Positions:

• chr2-151636257-C-T

Variant summary

Our verdict is Benign. Variant got -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BS1 BS2

The NM_001164508.2(NEB):​c.9072G>A​(p.Ala3024=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00181 in 1,610,126 control chromosomes in the GnomAD database, including 9 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0013 (1 hom., cov: 32)
  • Exomes 𝑓: 0.0019 (8 hom.)
• Consequence: NEB NM_001164508.2 synonymous
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:5
• Conservation: PhyloP100: -4.99

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 -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.57).
• BP6: Variant 2-151636257-C-T is Benign according to our data. Variant chr2-151636257-C-T is described in ClinVar as [Likely_benign]. Clinvar id is 257837.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=-4.99 with no splicing effect.
• BS1: Variant frequency is greater than expected in population sas. gnomad4_exome allele frequency = 0.00185 (2704/1457790) while in subpopulation SAS AF= 0.00379 (327/86238). AF 95% confidence interval is 0.00345. There are 8 homozygotes in gnomad4_exome. There are 1430 alleles in male gnomad4_exome subpopulation. Median coverage is 30. This position pass quality control queck.
• BS2: High Homozygotes in GnomAdExome4 at 8 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
NEB	NM_001164507.2	c.9072G>A	p.Ala3024=	synonymous_variant	64/182	ENST00000427231.7	NP_001157979.2
NEB	NM_001164508.2	c.9072G>A	p.Ala3024=	synonymous_variant	64/182	ENST00000397345.8	NP_001157980.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
NEB	ENST00000397345.8	c.9072G>A	p.Ala3024=	synonymous_variant	64/182	5	NM_001164508.2	ENSP00000380505	P5
NEB	ENST00000427231.7	c.9072G>A	p.Ala3024=	synonymous_variant	64/182	5	NM_001164507.2	ENSP00000416578	A2
NEB	ENST00000409198.5	c.8853+3636G>A		intron_variant		5		ENSP00000386259

Frequencies

GnomAD3 genomes AF: 0.00135 AC: 205 AN: 152218 Hom.: 1 Cov.: 32

Gnomad AFR AF: 0.000314

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00111

Gnomad ASJ AF: 0.0104

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00332

Gnomad FIN AF: 0.0000941

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00170

Gnomad OTH AF: 0.00287

GnomAD3 exomes AF: 0.00245 AC: 604 AN: 246110 Hom.: 6 AF XY: 0.00269 AC XY: 360 AN XY: 133740

Gnomad AFR exome AF: 0.000324

Gnomad AMR exome AF: 0.00290

Gnomad ASJ exome AF: 0.0110

Gnomad EAS exome AF: 0.0000559

Gnomad SAS exome AF: 0.00409

Gnomad FIN exome AF: 0.0000527

Gnomad NFE exome AF: 0.00214

Gnomad OTH exome AF: 0.00333

GnomAD4 exome AF: 0.00185 AC: 2704 AN: 1457790 Hom.: 8 Cov.: 30 AF XY: 0.00197 AC XY: 1430 AN XY: 725304

Gnomad4 AFR exome AF: 0.000269

Gnomad4 AMR exome AF: 0.00297

Gnomad4 ASJ exome AF: 0.00961

Gnomad4 EAS exome AF: 0.0000756

Gnomad4 SAS exome AF: 0.00379

Gnomad4 FIN exome AF: 0.000121

Gnomad4 NFE exome AF: 0.00167

Gnomad4 OTH exome AF: 0.00186

GnomAD4 genome AF: 0.00135 AC: 205 AN: 152336 Hom.: 1 Cov.: 32 AF XY: 0.00137 AC XY: 102 AN XY: 74492

Gnomad4 AFR AF: 0.000313

Gnomad4 AMR AF: 0.00111

Gnomad4 ASJ AF: 0.0104

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00332

Gnomad4 FIN AF: 0.0000941

Gnomad4 NFE AF: 0.00170

Gnomad4 OTH AF: 0.00284

Alfa AF: 0.00258 Hom.: 0

Bravo AF: 0.00162

Asia WGS AF: 0.000289 AC: 1 AN: 3478

EpiCase AF: 0.00327

EpiControl AF: 0.00320

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:5

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Benign, criteria provided, single submitter	clinical testing	GeneDx	Mar 16, 2018	- -
Likely benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Feb 01, 2024	NEB: BP4, BP7, BS2 -

Nemaline myopathy 2 Benign:2

Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 31, 2024	- -
Benign, no assertion criteria provided	clinical testing	Natera, Inc.	Dec 05, 2019	- -

not specified Benign:1

Benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

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Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.57
CADD	Benign	0.061
DANN	Benign	0.64

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: rs369897667; hg19: chr2-152492771; COSMIC: COSV51136152;