NM_001164507.2:c.5763+35T>C

Variant names:

• chr2-151663513-A-G
• rs12620077
• NM_001164507.2:c.5763+35T>C

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_001164507.2(NEB):​c.5763+35T>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.204 in 1,560,008 control chromosomes in the GnomAD database, including 44,717 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.30 (9436 hom., cov: 32)
  • Exomes 𝑓: 0.19 (35281 hom.)
• Consequence: NEB NM_001164507.2 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:4
• Conservation: PhyloP100: 0.112

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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.81).
• BP6: Variant 2-151663513-A-G is Benign according to our data. Variant chr2-151663513-A-G is described in ClinVar as [Benign]. Clinvar id is 257822.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr2-151663513-A-G is described in Lovd as [Benign].
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.587 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
NEB	NM_001164507.2	c.5763+35T>C		intron_variant	Intron 45 of 181	ENST00000427231.7	NP_001157979.2
NEB	NM_001164508.2	c.5763+35T>C		intron_variant	Intron 45 of 181	ENST00000397345.8	NP_001157980.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
NEB	ENST00000397345.8	c.5763+35T>C		intron_variant	Intron 45 of 181	5	NM_001164508.2	ENSP00000380505.3
NEB	ENST00000427231.7	c.5763+35T>C		intron_variant	Intron 45 of 181	5	NM_001164507.2	ENSP00000416578.2
NEB	ENST00000409198.5	c.5763+35T>C		intron_variant	Intron 45 of 149	5		ENSP00000386259.1

Frequencies

GnomAD3 genomes AF: 0.295 AC: 44860 AN: 152044 Hom.: 9391 Cov.: 32

Gnomad AFR AF: 0.568

Gnomad AMI AF: 0.177

Gnomad AMR AF: 0.182

Gnomad ASJ AF: 0.259

Gnomad EAS AF: 0.604

Gnomad SAS AF: 0.336

Gnomad FIN AF: 0.131

Gnomad MID AF: 0.212

Gnomad NFE AF: 0.158

Gnomad OTH AF: 0.269

GnomAD3 exomes AF: 0.243 AC: 53262 AN: 219536 Hom.: 9280 AF XY: 0.239 AC XY: 28195 AN XY: 117736

Gnomad AFR exome AF: 0.584

Gnomad AMR exome AF: 0.136

Gnomad ASJ exome AF: 0.248

Gnomad EAS exome AF: 0.593

Gnomad SAS exome AF: 0.355

Gnomad FIN exome AF: 0.140

Gnomad NFE exome AF: 0.158

Gnomad OTH exome AF: 0.217

GnomAD4 exome AF: 0.194 AC: 272767 AN: 1407846 Hom.: 35281 Cov.: 30 AF XY: 0.196 AC XY: 136254 AN XY: 693796

Gnomad4 AFR exome AF: 0.587

Gnomad4 AMR exome AF: 0.143

Gnomad4 ASJ exome AF: 0.250

Gnomad4 EAS exome AF: 0.620

Gnomad4 SAS exome AF: 0.336

Gnomad4 FIN exome AF: 0.142

Gnomad4 NFE exome AF: 0.157

Gnomad4 OTH exome AF: 0.235

GnomAD4 genome AF: 0.295 AC: 44955 AN: 152162 Hom.: 9436 Cov.: 32 AF XY: 0.293 AC XY: 21816 AN XY: 74378

Gnomad4 AFR AF: 0.568

Gnomad4 AMR AF: 0.182

Gnomad4 ASJ AF: 0.259

Gnomad4 EAS AF: 0.604

Gnomad4 SAS AF: 0.336

Gnomad4 FIN AF: 0.131

Gnomad4 NFE AF: 0.158

Gnomad4 OTH AF: 0.277

Alfa AF: 0.227 Hom.: 1429

Bravo AF: 0.310

Asia WGS AF: 0.536 AC: 1861 AN: 3478

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	-0.81
CADD	Benign	0.83
DANN	Benign	0.49

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.060		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: rs12620077; hg19: chr2-152520027;