rs71415153

Variant names:

• chr2-151592049-A-G
• rs71415153
• NM_001164507.2:c.14811T>C

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.14811T>C​(p.Ala4937Ala) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00142 in 1,547,756 control chromosomes in the GnomAD database, including 42 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0029 (9 hom., cov: 31)
  • Exomes 𝑓: 0.0013 (33 hom.)
• Consequence: NEB NM_001164508.2 synonymous
• Clinical Significance: Likely benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: -0.139

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=-0.86).
• BP6: Variant 2-151592049-A-G is Benign according to our data. Variant chr2-151592049-A-G is described in ClinVar as [Likely_benign]. Clinvar id is 257745.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=-0.139 with no splicing effect.
• BS1: Variant frequency is greater than expected in population eas. gnomad4 allele frequency = 0.00294 (447/152098) while in subpopulation EAS AF= 0.0493 (255/5176). AF 95% confidence interval is 0.0443. There are 9 homozygotes in gnomad4. There are 251 alleles in male gnomad4 subpopulation. Median coverage is 31. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd4 at 9 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
NEB	NM_001164507.2	c.14811T>C	p.Ala4937Ala	synonymous_variant	Exon 95 of 182	ENST00000427231.7	NP_001157979.2
NEB	NM_001164508.2	c.14811T>C	p.Ala4937Ala	synonymous_variant	Exon 95 of 182	ENST00000397345.8	NP_001157980.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
NEB	ENST00000397345.8	c.14811T>C	p.Ala4937Ala	synonymous_variant	Exon 95 of 182	5	NM_001164508.2	ENSP00000380505.3
NEB	ENST00000427231.7	c.14811T>C	p.Ala4937Ala	synonymous_variant	Exon 95 of 182	5	NM_001164507.2	ENSP00000416578.2
NEB	ENST00000409198.5	c.11602-15695T>C		intron_variant	Intron 78 of 149	5		ENSP00000386259.1

Frequencies

GnomAD3 genomes AF: 0.00295 AC: 448 AN: 151984 Hom.: 9 Cov.: 31

Gnomad AFR AF: 0.00172

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00419

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.0499

Gnomad SAS AF: 0.00498

Gnomad FIN AF: 0.000282

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000338

Gnomad OTH AF: 0.00191

GnomAD3 exomes AF: 0.00327 AC: 510 AN: 156116 Hom.: 12 AF XY: 0.00320 AC XY: 265 AN XY: 82722

Gnomad AFR exome AF: 0.000252

Gnomad AMR exome AF: 0.00369

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.0362

Gnomad SAS exome AF: 0.000659

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000498

Gnomad OTH exome AF: 0.00205

GnomAD4 exome AF: 0.00126 AC: 1755 AN: 1395658 Hom.: 33 Cov.: 32 AF XY: 0.00129 AC XY: 887 AN XY: 688390

Gnomad4 AFR exome AF: 0.000573

Gnomad4 AMR exome AF: 0.00629

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.0297

Gnomad4 SAS exome AF: 0.00291

Gnomad4 FIN exome AF: 0.000162

Gnomad4 NFE exome AF: 0.0000714

Gnomad4 OTH exome AF: 0.00255

GnomAD4 genome AF: 0.00294 AC: 447 AN: 152098 Hom.: 9 Cov.: 31 AF XY: 0.00337 AC XY: 251 AN XY: 74406

Gnomad4 AFR AF: 0.00176

Gnomad4 AMR AF: 0.00419

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.0493

Gnomad4 SAS AF: 0.00498

Gnomad4 FIN AF: 0.000282

Gnomad4 NFE AF: 0.000338

Gnomad4 OTH AF: 0.00237

Alfa AF: 0.00186 Hom.: 1

ClinVar

Significance: Likely benign

Submissions summary: Benign:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Apr 19, 2021

GeneDx

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant is associated with the following publications: (PMID: 25203624) -

not specified Benign:1

-

PreventionGenetics, part of Exact Sciences

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.86
CADD	Benign	6.4
DANN	Benign	0.53

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: rs71415153; hg19: chr2-152448563;