chr2-151640574-G-A

Variant names:

• chr2-151640574-G-A
• rs61730771
• NM_001164507.2:c.8466C>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_001164508.2(NEB):​c.8466C>T​(p.His2822His) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0197 in 1,613,806 control chromosomes in the GnomAD database, including 458 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.025 (63 hom., cov: 32)
  • Exomes 𝑓: 0.019 (395 hom.)
• Consequence: NEB NM_001164508.2 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:12
• Conservation: PhyloP100: -2.48
• 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: 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=-0.58).
• BP6: Variant 2-151640574-G-A is Benign according to our data. Variant chr2-151640574-G-A is described in ClinVar as Benign. ClinVar VariationId is 129759.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=-2.48 with no splicing effect.
• BS1: Variant frequency is greater than expected in population sas. GnomAd4 allele frequency = 0.0247 (3755/152116) while in subpopulation SAS AF = 0.0455 (219/4816). AF 95% confidence interval is 0.0405. There are 63 homozygotes in GnomAd4. There are 1832 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 63 AD,AR gene

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.8466C>T	p.His2822His	synonymous	Exon 61 of 182	NP_001157979.2	P20929-3
	NEB	NM_001164508.2	MANE Select	c.8466C>T	p.His2822His	synonymous	Exon 61 of 182	NP_001157980.2	P20929-2
	NEB	NM_001271208.2		c.8466C>T	p.His2822His	synonymous	Exon 61 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.8466C>T	p.His2822His	synonymous	Exon 61 of 182	ENSP00000380505.3	P20929-2
	NEB	ENST00000427231.7	TSL:5 MANE Plus Clinical	c.8466C>T	p.His2822His	synonymous	Exon 61 of 182	ENSP00000416578.2	P20929-3
	NEB	ENST00000409198.5	TSL:5	c.8466C>T	p.His2822His	synonymous	Exon 61 of 150	ENSP00000386259.1	P20929-4

Frequencies

GnomAD3 genomes AF: 0.0246 AC: 3744 AN: 151998 Hom.: 63 Cov.: 32

Gnomad AFR AF: 0.0415

Gnomad AMI AF: 0.0241

Gnomad AMR AF: 0.0159

Gnomad ASJ AF: 0.0427

Gnomad EAS AF: 0.00444

Gnomad SAS AF: 0.0446

Gnomad FIN AF: 0.0123

Gnomad MID AF: 0.0411

Gnomad NFE AF: 0.0173

Gnomad OTH AF: 0.0273

GnomAD2 exomes AF: 0.0211 AC: 5256 AN: 249214 AF XY: 0.0223

Gnomad AFR exome AF: 0.0462

Gnomad AMR exome AF: 0.00857

Gnomad ASJ exome AF: 0.0467

Gnomad EAS exome AF: 0.00406

Gnomad FIN exome AF: 0.0130

Gnomad NFE exome AF: 0.0168

Gnomad OTH exome AF: 0.0200

GnomAD4 exome AF: 0.0192 AC: 27994 AN: 1461690 Hom.: 395 Cov.: 32 AF XY: 0.0200 AC XY: 14566 AN XY: 727130

African (AFR) AF: 0.0456 AC: 1527 AN: 33480

American (AMR) AF: 0.00953 AC: 426 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.0468 AC: 1224 AN: 26134

East Asian (EAS) AF: 0.00186 AC: 74 AN: 39700

South Asian (SAS) AF: 0.0473 AC: 4084 AN: 86258

European-Finnish (FIN) AF: 0.0124 AC: 663 AN: 53402

Middle Eastern (MID) AF: 0.0290 AC: 167 AN: 5768

European-Non Finnish (NFE) AF: 0.0165 AC: 18361 AN: 1111850

Other (OTH) AF: 0.0243 AC: 1468 AN: 60374

GnomAD4 genome AF: 0.0247 AC: 3755 AN: 152116 Hom.: 63 Cov.: 32 AF XY: 0.0246 AC XY: 1832 AN XY: 74346

African (AFR) AF: 0.0415 AC: 1724 AN: 41508

American (AMR) AF: 0.0158 AC: 241 AN: 15280

Ashkenazi Jewish (ASJ) AF: 0.0427 AC: 148 AN: 3468

East Asian (EAS) AF: 0.00445 AC: 23 AN: 5164

South Asian (SAS) AF: 0.0455 AC: 219 AN: 4816

European-Finnish (FIN) AF: 0.0123 AC: 130 AN: 10580

Middle Eastern (MID) AF: 0.0442 AC: 13 AN: 294

European-Non Finnish (NFE) AF: 0.0173 AC: 1178 AN: 67986

Other (OTH) AF: 0.0270 AC: 57 AN: 2108

Alfa AF: 0.0181 Hom.: 11

Bravo AF: 0.0250

Asia WGS AF: 0.0410 AC: 142 AN: 3478

EpiCase AF: 0.0178

EpiControl AF: 0.0200

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	6	not specified (6)
-	-	3	Nemaline myopathy 2 (3)
-	-	3	not provided (3)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.58
CADD	Benign	0.68
DANN	Benign	0.50
PhyloP100		-2.5
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: rs61730771; hg19: chr2-152497088; COSMIC: COSV51417544;