rs34555492

Variant names:

• chr2-151540718-G-A
• rs34555492
• NM_001164507.2:c.20766C>T

Your query was ambiguous. Multiple possible variants found:

• chr2-151540718-G-A
• chr2-151540718-G-C
• chr2-151540718-G-T

Variant summary

Our verdict is Benign. The variant received -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BS1 BS2

The NM_001271208.2(NEB):​c.20766C>T​(p.Asp6922Asp) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0194 in 1,613,436 control chromosomes in the GnomAD database, including 400 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.013 (23 hom., cov: 32)
  • Exomes 𝑓: 0.020 (377 hom.)
• Consequence: NEB NM_001271208.2 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:11
• Conservation: PhyloP100: -2.22
• Publications: 3 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

LOC124906081 (HGNC:):

ACMG classification

Our verdict: Benign. The variant received -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.75).
• BP6: Variant 2-151540718-G-A is Benign according to our data. Variant chr2-151540718-G-A is described in ClinVar as Benign. ClinVar VariationId is 129723.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=-2.22 with no splicing effect.
• BS1: Variant frequency is greater than expected in population sas. GnomAd4 allele frequency = 0.0131 (1997/152210) while in subpopulation SAS AF = 0.038 (183/4820). AF 95% confidence interval is 0.0335. There are 23 homozygotes in GnomAd4. There are 928 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 23 AD,AR gene

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001271208.2. 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.20766C>T	p.Asp6922Asp	synonymous	Exon 137 of 182	NP_001157979.2
	NEB	NM_001164508.2	MANE Select	c.20766C>T	p.Asp6922Asp	synonymous	Exon 137 of 182	NP_001157980.2
	NEB	NM_001271208.2		c.20766C>T	p.Asp6922Asp	synonymous	Exon 137 of 183	NP_001258137.2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	NEB	ENST00000397345.8	TSL:5 MANE Select	c.20766C>T	p.Asp6922Asp	synonymous	Exon 137 of 182	ENSP00000380505.3
	NEB	ENST00000427231.7	TSL:5 MANE Plus Clinical	c.20766C>T	p.Asp6922Asp	synonymous	Exon 137 of 182	ENSP00000416578.2
	NEB	ENST00000409198.5	TSL:5	c.15663C>T	p.Asp5221Asp	synonymous	Exon 110 of 150	ENSP00000386259.1

Frequencies

GnomAD3 genomes AF: 0.0131 AC: 2000 AN: 152092 Hom.: 23 Cov.: 32

Gnomad AFR AF: 0.00418

Gnomad AMI AF: 0.00877

Gnomad AMR AF: 0.00819

Gnomad ASJ AF: 0.00173

Gnomad EAS AF: 0.000193

Gnomad SAS AF: 0.0381

Gnomad FIN AF: 0.00462

Gnomad MID AF: 0.0285

Gnomad NFE AF: 0.0209

Gnomad OTH AF: 0.0105

GnomAD2 exomes AF: 0.0154 AC: 3840 AN: 248722 AF XY: 0.0174

Gnomad AFR exome AF: 0.00362

Gnomad AMR exome AF: 0.00467

Gnomad ASJ exome AF: 0.00109

Gnomad EAS exome AF: 0.0000557

Gnomad FIN exome AF: 0.00539

Gnomad NFE exome AF: 0.0193

Gnomad OTH exome AF: 0.0123

GnomAD4 exome AF: 0.0201 AC: 29301 AN: 1461226 Hom.: 377 Cov.: 31 AF XY: 0.0206 AC XY: 14997 AN XY: 726904

African (AFR) AF: 0.00350 AC: 117 AN: 33452

American (AMR) AF: 0.00476 AC: 213 AN: 44712

Ashkenazi Jewish (ASJ) AF: 0.000727 AC: 19 AN: 26122

East Asian (EAS) AF: 0.000151 AC: 6 AN: 39678

South Asian (SAS) AF: 0.0397 AC: 3422 AN: 86242

European-Finnish (FIN) AF: 0.00648 AC: 346 AN: 53390

Middle Eastern (MID) AF: 0.0170 AC: 98 AN: 5760

European-Non Finnish (NFE) AF: 0.0216 AC: 23968 AN: 1111524

Other (OTH) AF: 0.0184 AC: 1112 AN: 60346

GnomAD4 genome AF: 0.0131 AC: 1997 AN: 152210 Hom.: 23 Cov.: 32 AF XY: 0.0125 AC XY: 928 AN XY: 74418

African (AFR) AF: 0.00417 AC: 173 AN: 41524

American (AMR) AF: 0.00818 AC: 125 AN: 15280

Ashkenazi Jewish (ASJ) AF: 0.00173 AC: 6 AN: 3472

East Asian (EAS) AF: 0.000193 AC: 1 AN: 5180

South Asian (SAS) AF: 0.0380 AC: 183 AN: 4820

European-Finnish (FIN) AF: 0.00462 AC: 49 AN: 10610

Middle Eastern (MID) AF: 0.0238 AC: 7 AN: 294

European-Non Finnish (NFE) AF: 0.0209 AC: 1423 AN: 68004

Other (OTH) AF: 0.0104 AC: 22 AN: 2114

Alfa AF: 0.0172 Hom.: 64

Bravo AF: 0.0120

Asia WGS AF: 0.00866 AC: 30 AN: 3478

EpiCase AF: 0.0184

EpiControl AF: 0.0173

ClinVar

ClinVar submissions as Germline

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	5	not specified (5)
-	-	4	Nemaline myopathy 2 (4)
-	-	1	Arthrogryposis multiplex congenita 6 (1)
-	-	1	not provided (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.75
CADD	Benign	0.052
DANN	Benign	0.49
PhyloP100		-2.2
Mutation Taster		=98/2	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: rs34555492; hg19: chr2-152397232;