chr2-151695548-A-C

Variant names:

• chr2-151695548-A-C
• rs6433569
• NM_001164507.2:c.1674+30T>G

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_001164508.2(NEB):​c.1674+30T>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.767 in 1,526,238 control chromosomes in the GnomAD database, including 468,528 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.63 (35798 hom., cov: 32)
  • Exomes 𝑓: 0.78 (432730 hom.)
• Consequence: NEB NM_001164508.2 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:4
• Conservation: PhyloP100: 0.152

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

Our verdict: Benign. The variant received -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.86).
• BP6: Variant 2-151695548-A-C is Benign according to our data. Variant chr2-151695548-A-C is described in ClinVar as [Benign]. Clinvar id is 257767.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr2-151695548-A-C is described in Lovd as [Benign].
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.816 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
NEB	NM_001164507.2	c.1674+30T>G		intron_variant	Intron 18 of 181	ENST00000427231.7	NP_001157979.2
NEB	NM_001164508.2	c.1674+30T>G		intron_variant	Intron 18 of 181	ENST00000397345.8	NP_001157980.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
NEB	ENST00000397345.8	c.1674+30T>G		intron_variant	Intron 18 of 181	5	NM_001164508.2	ENSP00000380505.3
NEB	ENST00000427231.7	c.1674+30T>G		intron_variant	Intron 18 of 181	5	NM_001164507.2	ENSP00000416578.2
NEB	ENST00000489048.1	n.573+30T>G		intron_variant	Intron 6 of 11	1
NEB	ENST00000409198.5	c.1674+30T>G		intron_variant	Intron 18 of 149	5		ENSP00000386259.1

Frequencies

GnomAD3 genomes AF: 0.628 AC: 95503 AN: 152034 Hom.: 35795 Cov.: 32

Gnomad AFR AF: 0.206

Gnomad AMI AF: 0.815

Gnomad AMR AF: 0.783

Gnomad ASJ AF: 0.726

Gnomad EAS AF: 0.394

Gnomad SAS AF: 0.641

Gnomad FIN AF: 0.859

Gnomad MID AF: 0.728

Gnomad NFE AF: 0.822

Gnomad OTH AF: 0.679

GnomAD2 exomes AF: 0.733 AC: 175634 AN: 239766 AF XY: 0.737

Gnomad AFR exome AF: 0.189

Gnomad AMR exome AF: 0.849

Gnomad ASJ exome AF: 0.734

Gnomad EAS exome AF: 0.412

Gnomad FIN exome AF: 0.851

Gnomad NFE exome AF: 0.824

Gnomad OTH exome AF: 0.768

GnomAD4 exome AF: 0.783 AC: 1075274 AN: 1374086 Hom.: 432730 Cov.: 20 AF XY: 0.780 AC XY: 536378 AN XY: 687496

Gnomad4 AFR exome AF: 0.186 AC: 5843 AN: 31388

Gnomad4 AMR exome AF: 0.840 AC: 36127 AN: 43022

Gnomad4 ASJ exome AF: 0.735 AC: 18748 AN: 25500

Gnomad4 EAS exome AF: 0.385 AC: 15035 AN: 39060

Gnomad4 SAS exome AF: 0.646 AC: 53090 AN: 82168

Gnomad4 FIN exome AF: 0.849 AC: 45157 AN: 53218

Gnomad4 NFE exome AF: 0.824 AC: 854656 AN: 1036628

Gnomad4 Remaining exome AF: 0.738 AC: 42404 AN: 57494

GnomAD4 genome AF: 0.628 AC: 95499 AN: 152152 Hom.: 35798 Cov.: 32 AF XY: 0.633 AC XY: 47053 AN XY: 74386

Gnomad4 AFR AF: 0.205 AC: 0.20524 AN: 0.20524

Gnomad4 AMR AF: 0.783 AC: 0.783098 AN: 0.783098

Gnomad4 ASJ AF: 0.726 AC: 0.725648 AN: 0.725648

Gnomad4 EAS AF: 0.394 AC: 0.39374 AN: 0.39374

Gnomad4 SAS AF: 0.641 AC: 0.641435 AN: 0.641435

Gnomad4 FIN AF: 0.859 AC: 0.858708 AN: 0.858708

Gnomad4 NFE AF: 0.822 AC: 0.821966 AN: 0.821966

Gnomad4 OTH AF: 0.671 AC: 0.670616 AN: 0.670616

Alfa AF: 0.632 Hom.: 7343

Bravo AF: 0.605

Asia WGS AF: 0.446 AC: 1553 AN: 3476

ClinVar

Significance: Benign

Submissions summary: Benign:4

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:1

-

PreventionGenetics, part of Exact Sciences

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

not provided Benign:1

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Nemaline myopathy 2 Benign:1

Jul 10, 2021

Genome-Nilou Lab

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Arthrogryposis multiplex congenita 6 Benign:1

Jul 10, 2021

Genome-Nilou Lab

Significance: 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	8.8
DANN	Benign	0.58
Mutation Taster		=100/0	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.12		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: rs6433569; hg19: chr2-152552062; COSMIC: COSV50869589;