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. The variant received -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
• Publications: 6 publications found

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]

NEB Gene-Disease associations (from GenCC):

• nemaline myopathy 2

  Inheritance: AR, AD Classification: DEFINITIVE, STRONG, LIMITED Submitted by: ClinGen, Labcorp Genetics (formerly Invitae), Myriad Women’s Health, G2P, Ambry Genetics
• childhood-onset nemaline myopathy

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• intermediate nemaline myopathy

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• typical nemaline myopathy

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• lethal multiple pterygium syndrome

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet
• severe congenital nemaline myopathy

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Benign. The variant received -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 VariationId is 257822.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• 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

GnomAD2 exomes AF: 0.243 AC: 53262 AN: 219536 AF XY: 0.239

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 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

African (AFR) AF: 0.587 AC: 18904 AN: 32178

American (AMR) AF: 0.143 AC: 5919 AN: 41248

Ashkenazi Jewish (ASJ) AF: 0.250 AC: 5838 AN: 23334

East Asian (EAS) AF: 0.620 AC: 24210 AN: 39050

South Asian (SAS) AF: 0.336 AC: 26234 AN: 78174

European-Finnish (FIN) AF: 0.142 AC: 7351 AN: 51672

Middle Eastern (MID) AF: 0.220 AC: 1215 AN: 5512

European-Non Finnish (NFE) AF: 0.157 AC: 169462 AN: 1078626

Other (OTH) AF: 0.235 AC: 13634 AN: 58052

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

African (AFR) AF: 0.568 AC: 23568 AN: 41464

American (AMR) AF: 0.182 AC: 2783 AN: 15292

Ashkenazi Jewish (ASJ) AF: 0.259 AC: 898 AN: 3472

East Asian (EAS) AF: 0.604 AC: 3122 AN: 5166

South Asian (SAS) AF: 0.336 AC: 1618 AN: 4822

European-Finnish (FIN) AF: 0.131 AC: 1389 AN: 10608

Middle Eastern (MID) AF: 0.201 AC: 59 AN: 294

European-Non Finnish (NFE) AF: 0.158 AC: 10770 AN: 68016

Other (OTH) AF: 0.277 AC: 587 AN: 2116

Alfa AF: 0.218 Hom.: 1993

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
PhyloP100		0.11
Mutation Taster		=100/0	polymorphism (auto)

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

Other links and lift over

dbSNP: rs12620077; hg19: chr2-152520027;