2-151633705-A-G

Variant names:

• chr2-151633705-A-G
• rs6709886
• NM_001164507.2:c.9363T>C

Variant summary

Our verdict is Benign. The variant received -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BA1

The NM_001164508.2(NEB):​c.9363T>C​(p.Pro3121Pro) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.64 in 1,613,716 control chromosomes in the GnomAD database, including 333,017 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Synonymous variant affecting the same amino acid position (i.e. P3121P) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.62 (29455 hom., cov: 32)
  • Exomes 𝑓: 0.64 (303562 hom.)
• Consequence: NEB NM_001164508.2 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:9
• Conservation: PhyloP100: -4.57
• Publications: 13 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 -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.85).
• BP6: Variant 2-151633705-A-G is Benign according to our data. Variant chr2-151633705-A-G is described in ClinVar as Benign. ClinVar VariationId is 226848.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=-4.57 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.771 is higher than 0.05.

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.9363T>C	p.Pro3121Pro	synonymous	Exon 65 of 182	NP_001157979.2	P20929-3
	NEB	NM_001164508.2	MANE Select	c.9363T>C	p.Pro3121Pro	synonymous	Exon 65 of 182	NP_001157980.2	P20929-2
	NEB	NM_001271208.2		c.9363T>C	p.Pro3121Pro	synonymous	Exon 65 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.9363T>C	p.Pro3121Pro	synonymous	Exon 65 of 182	ENSP00000380505.3	P20929-2
	NEB	ENST00000427231.7	TSL:5 MANE Plus Clinical	c.9363T>C	p.Pro3121Pro	synonymous	Exon 65 of 182	ENSP00000416578.2	P20929-3
	NEB	ENST00000409198.5	TSL:5	c.8854-2527T>C		intron	N/A	ENSP00000386259.1	P20929-4

Frequencies

GnomAD3 genomes AF: 0.616 AC: 93665 AN: 151936 Hom.: 29412 Cov.: 32

Gnomad AFR AF: 0.519

Gnomad AMI AF: 0.505

Gnomad AMR AF: 0.716

Gnomad ASJ AF: 0.514

Gnomad EAS AF: 0.792

Gnomad SAS AF: 0.557

Gnomad FIN AF: 0.658

Gnomad MID AF: 0.639

Gnomad NFE AF: 0.644

Gnomad OTH AF: 0.623

GnomAD2 exomes AF: 0.644 AC: 160331 AN: 249022 AF XY: 0.636

Gnomad AFR exome AF: 0.522

Gnomad AMR exome AF: 0.757

Gnomad ASJ exome AF: 0.520

Gnomad EAS exome AF: 0.795

Gnomad FIN exome AF: 0.652

Gnomad NFE exome AF: 0.638

Gnomad OTH exome AF: 0.651

GnomAD4 exome AF: 0.642 AC: 938382 AN: 1461662 Hom.: 303562 Cov.: 102 AF XY: 0.638 AC XY: 464202 AN XY: 727098

African (AFR) AF: 0.524 AC: 17535 AN: 33480

American (AMR) AF: 0.748 AC: 33441 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.520 AC: 13581 AN: 26134

East Asian (EAS) AF: 0.823 AC: 32680 AN: 39700

South Asian (SAS) AF: 0.541 AC: 46670 AN: 86254

European-Finnish (FIN) AF: 0.654 AC: 34934 AN: 53402

Middle Eastern (MID) AF: 0.622 AC: 3586 AN: 5768

European-Non Finnish (NFE) AF: 0.645 AC: 717420 AN: 1111832

Other (OTH) AF: 0.638 AC: 38535 AN: 60368

GnomAD4 genome AF: 0.617 AC: 93767 AN: 152054 Hom.: 29455 Cov.: 32 AF XY: 0.620 AC XY: 46072 AN XY: 74312

African (AFR) AF: 0.519 AC: 21521 AN: 41444

American (AMR) AF: 0.717 AC: 10959 AN: 15290

Ashkenazi Jewish (ASJ) AF: 0.514 AC: 1783 AN: 3470

East Asian (EAS) AF: 0.792 AC: 4089 AN: 5166

South Asian (SAS) AF: 0.558 AC: 2688 AN: 4818

European-Finnish (FIN) AF: 0.658 AC: 6947 AN: 10560

Middle Eastern (MID) AF: 0.629 AC: 185 AN: 294

European-Non Finnish (NFE) AF: 0.644 AC: 43805 AN: 67986

Other (OTH) AF: 0.629 AC: 1329 AN: 2114

Alfa AF: 0.567 Hom.: 3294

Bravo AF: 0.619

Asia WGS AF: 0.679 AC: 2362 AN: 3478

EpiCase AF: 0.627

EpiControl AF: 0.631

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	3	Nemaline myopathy 2 (3)
-	-	3	not specified (3)
-	-	2	not provided (2)
-	-	1	Arthrogryposis multiplex congenita 6 (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.85
CADD	Benign	0.017
DANN	Benign	0.34
PhyloP100		-4.6
Mutation Taster		=88/12	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: rs6709886; hg19: chr2-152490219; COSMIC: COSV108037723;