rs62174689

Variant names:

• chr2-151579326-C-G
• rs62174689
• NM_001164507.2:c.16704+12G>C

Your query was ambiguous. Multiple possible variants found:

• chr2-151579326-C-G
• chr2-151579326-C-A
• chr2-151579326-C-T

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BP6_Very_Strong

The NM_001164508.2(NEB):​c.16704+12G>C variant causes a intron change involving the alteration of a non-conserved nucleotide. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.34 (7602 hom., cov: 18)
  • Exomes 𝑓: 0.098 (38950 hom.)
  • Failed GnomAD Quality Control
• Consequence: NEB NM_001164508.2 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: -1.25
• Publications: 1 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: G2P, Ambry Genetics, Labcorp Genetics (formerly Invitae), Myriad Women’s Health, ClinGen
• autosomal dominant nebulin-related myopathy

  Inheritance: AD Classification: MODERATE Submitted by: ClinGen
• 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 -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.84).
• BP6: Variant 2-151579326-C-G is Benign according to our data. Variant chr2-151579326-C-G is described in ClinVar as Benign. ClinVar VariationId is 257766.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001164508.2. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	NEB	NM_001164507.2	MANE Plus Clinical	c.16704+12G>C		intron	N/A	NP_001157979.2	P20929-3
	NEB	NM_001164508.2	MANE Select	c.16704+12G>C		intron	N/A	NP_001157980.2	P20929-2
	NEB	NM_001271208.2		c.16704+12G>C		intron	N/A	NP_001258137.2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	NEB	ENST00000397345.8	TSL:5 MANE Select	c.16704+12G>C		intron	N/A	ENSP00000380505.3	P20929-2
	NEB	ENST00000427231.7	TSL:5 MANE Plus Clinical	c.16704+12G>C		intron	N/A	ENSP00000416578.2	P20929-3
	NEB	ENST00000409198.5	TSL:5	c.11602-2972G>C		intron	N/A	ENSP00000386259.1	P20929-4

Frequencies

GnomAD3 genomes AF: 0.337 AC: 33722 AN: 100138 Hom.: 7608 Cov.: 18

Gnomad AFR AF: 0.124

Gnomad AMI AF: 0.399

Gnomad AMR AF: 0.468

Gnomad ASJ AF: 0.353

Gnomad EAS AF: 0.456

Gnomad SAS AF: 0.252

Gnomad FIN AF: 0.328

Gnomad MID AF: 0.526

Gnomad NFE AF: 0.485

Gnomad OTH AF: 0.323

GnomAD2 exomes AF: 0.0314 AC: 3303 AN: 105038 AF XY: 0.0309

Gnomad AFR exome AF: 0.00290

Gnomad AMR exome AF: 0.114

Gnomad ASJ exome AF: 0.00402

Gnomad EAS exome AF: 0.0665

Gnomad FIN exome AF: 0.00415

Gnomad NFE exome AF: 0.0167

Gnomad OTH exome AF: 0.0399

GnomAD4 exome Data not reliable, filtered out with message: AS_VQSR AF: 0.0985 AC: 83454 AN: 847584 Hom.: 38950 Cov.: 29 AF XY: 0.103 AC XY: 43130 AN XY: 418696

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.0135 AC: 380 AN: 28178

American (AMR) AF: 0.303 AC: 5764 AN: 19042

Ashkenazi Jewish (ASJ) AF: 0.0907 AC: 1533 AN: 16910

East Asian (EAS) AF: 0.347 AC: 6569 AN: 18924

South Asian (SAS) AF: 0.0997 AC: 5763 AN: 57792

European-Finnish (FIN) AF: 0.314 AC: 8128 AN: 25886

Middle Eastern (MID) AF: 0.118 AC: 303 AN: 2558

European-Non Finnish (NFE) AF: 0.0792 AC: 50904 AN: 642738

Other (OTH) AF: 0.116 AC: 4110 AN: 35556

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome Data not reliable, filtered out with message: AS_VQSR AF: 0.336 AC: 33695 AN: 100218 Hom.: 7602 Cov.: 18 AF XY: 0.324 AC XY: 15374 AN XY: 47378

⚠️ The allele balance in gnomAD version 4 Genomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.124 AC: 4328 AN: 34848

American (AMR) AF: 0.469 AC: 3733 AN: 7966

Ashkenazi Jewish (ASJ) AF: 0.353 AC: 896 AN: 2538

East Asian (EAS) AF: 0.455 AC: 1478 AN: 3248

South Asian (SAS) AF: 0.251 AC: 840 AN: 3348

European-Finnish (FIN) AF: 0.328 AC: 1519 AN: 4630

Middle Eastern (MID) AF: 0.509 AC: 108 AN: 212

European-Non Finnish (NFE) AF: 0.485 AC: 20127 AN: 41494

Other (OTH) AF: 0.316 AC: 402 AN: 1272

⚠️ The allele balance in gnomAD version 4 Genomes is significantly skewed from the expected value of 0.5. (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

Alfa AF: 0.278 Hom.: 778

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	2	not specified (2)
-	-	1	not provided (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.84
CADD	Benign	1.2
DANN	Benign	0.78
PhyloP100		-1.2
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: rs62174689; hg19: chr2-152435840; COSMIC: COSV51458385;