NM_001164507.2:c.19206+46C>A

Variant names:

• chr2-151560958-G-T
• rs76261031
• NM_001164507.2:c.19206+46C>A

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The NM_001164507.2(NEB):​c.19206+46C>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0214 in 1,176,964 control chromosomes in the GnomAD database, including 325 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.025 (61 hom., cov: 32)
  • Exomes 𝑓: 0.021 (264 hom.)
• Consequence: NEB NM_001164507.2 intron
• Clinical Significance: Likely benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -0.411
• Publications: 2 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=-0.86).
• BP6: Variant 2-151560958-G-T is Benign according to our data. Variant chr2-151560958-G-T is described in ClinVar as Likely_benign. ClinVar VariationId is 257778.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.0248 (3765/151758) while in subpopulation AFR AF = 0.0379 (1569/41384). AF 95% confidence interval is 0.0364. There are 61 homozygotes in GnomAd4. There are 1859 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 61 AD,AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
NEB	NM_001164507.2	c.19206+46C>A		intron_variant	Intron 123 of 181	ENST00000427231.7	NP_001157979.2
NEB	NM_001164508.2	c.19206+46C>A		intron_variant	Intron 123 of 181	ENST00000397345.8	NP_001157980.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
NEB	ENST00000397345.8	c.19206+46C>A		intron_variant	Intron 123 of 181	5	NM_001164508.2	ENSP00000380505.3
NEB	ENST00000427231.7	c.19206+46C>A		intron_variant	Intron 123 of 181	5	NM_001164507.2	ENSP00000416578.2

Frequencies

GnomAD3 genomes AF: 0.0248 AC: 3754 AN: 151640 Hom.: 61 Cov.: 32

Gnomad AFR AF: 0.0377

Gnomad AMI AF: 0.00110

Gnomad AMR AF: 0.0122

Gnomad ASJ AF: 0.0285

Gnomad EAS AF: 0.000195

Gnomad SAS AF: 0.00522

Gnomad FIN AF: 0.0407

Gnomad MID AF: 0.0190

Gnomad NFE AF: 0.0206

Gnomad OTH AF: 0.0241

GnomAD2 exomes AF: 0.0193 AC: 3631 AN: 188430 AF XY: 0.0187

Gnomad AFR exome AF: 0.0350

Gnomad AMR exome AF: 0.00892

Gnomad ASJ exome AF: 0.0200

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.0355

Gnomad NFE exome AF: 0.0224

Gnomad OTH exome AF: 0.0221

GnomAD4 exome AF: 0.0209 AC: 21430 AN: 1025206 Hom.: 264 Cov.: 13 AF XY: 0.0201 AC XY: 10519 AN XY: 523408

African (AFR) AF: 0.0375 AC: 910 AN: 24294

American (AMR) AF: 0.00997 AC: 343 AN: 34396

Ashkenazi Jewish (ASJ) AF: 0.0231 AC: 493 AN: 21372

East Asian (EAS) AF: 0.0000268 AC: 1 AN: 37296

South Asian (SAS) AF: 0.00688 AC: 466 AN: 67716

European-Finnish (FIN) AF: 0.0350 AC: 1784 AN: 50930

Middle Eastern (MID) AF: 0.00957 AC: 34 AN: 3554

European-Non Finnish (NFE) AF: 0.0222 AC: 16462 AN: 740002

Other (OTH) AF: 0.0205 AC: 937 AN: 45646

GnomAD4 genome AF: 0.0248 AC: 3765 AN: 151758 Hom.: 61 Cov.: 32 AF XY: 0.0251 AC XY: 1859 AN XY: 74194

African (AFR) AF: 0.0379 AC: 1569 AN: 41384

American (AMR) AF: 0.0122 AC: 186 AN: 15250

Ashkenazi Jewish (ASJ) AF: 0.0285 AC: 99 AN: 3468

East Asian (EAS) AF: 0.000195 AC: 1 AN: 5124

South Asian (SAS) AF: 0.00523 AC: 25 AN: 4784

European-Finnish (FIN) AF: 0.0407 AC: 429 AN: 10552

Middle Eastern (MID) AF: 0.0170 AC: 5 AN: 294

European-Non Finnish (NFE) AF: 0.0206 AC: 1400 AN: 67890

Other (OTH) AF: 0.0238 AC: 50 AN: 2100

Alfa AF: 0.0213 Hom.: 54

Bravo AF: 0.0236

ClinVar

Significance: Likely benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:1

-

PreventionGenetics, part of Exact Sciences

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

not provided Benign:1

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.86
CADD	Benign	0.84
DANN	Benign	0.49
PhyloP100		-0.41
Mutation Taster		=100/0	polymorphism (auto)

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

Other links and lift over

dbSNP: rs76261031; hg19: chr2-152417472;