2-151607546-C-A

Variant names:

• chr2-151607546-C-A
• rs763783436
• NM_001164507.2:c.12597G>T

Variant summary

Our verdict is Likely benign. The variant received -5 ACMG points: 0P and 5B. BP4_Strong BP7

The ENST00000397345.8(NEB):​c.12597G>T​(p.Pro4199Pro) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Synonymous variant affecting the same amino acid position (i.e. P4199P) has been classified as Likely benign.

• Frequency:
  • Genomes: not found (cov: 11)
  • Exomes 𝑓: 0.0000032 (1 hom.)
• Consequence: NEB ENST00000397345.8 synonymous
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -1.44
• Publications: 0 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: Likely_benign. The variant received -5 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.66).
• BP7: Synonymous conserved (PhyloP=-1.44 with no splicing effect.

Variant Effect in Transcripts

ACMG analysis was done for transcript: ENST00000397345.8. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	NEB	NM_001164507.2	MANE Plus Clinical	c.12597G>T	p.Pro4199Pro	synonymous	Exon 83 of 182	NP_001157979.2
	NEB	NM_001164508.2	MANE Select	c.12597G>T	p.Pro4199Pro	synonymous	Exon 83 of 182	NP_001157980.2
	NEB	NM_001271208.2		c.12597G>T	p.Pro4199Pro	synonymous	Exon 83 of 183	NP_001258137.2

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	NEB	ENST00000397345.8	TSL:5 MANE Select	c.12597G>T	p.Pro4199Pro	synonymous	Exon 83 of 182	ENSP00000380505.3
	NEB	ENST00000427231.7	TSL:5 MANE Plus Clinical	c.12597G>T	p.Pro4199Pro	synonymous	Exon 83 of 182	ENSP00000416578.2
	NEB	ENST00000409198.5	TSL:5	c.11601+2263G>T		intron	N/A	ENSP00000386259.1

Frequencies

GnomAD3 genomes Cov.: 11

GnomAD4 exome AF: 0.00000323 AC: 2 AN: 619510 Hom.: 1 Cov.: 7 AF XY: 0.00 AC XY: 0 AN XY: 318566

African (AFR) AF: 0.00 AC: 0 AN: 27398

American (AMR) AF: 0.00 AC: 0 AN: 17158

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 17798

East Asian (EAS) AF: 0.00 AC: 0 AN: 19478

South Asian (SAS) AF: 0.00 AC: 0 AN: 58198

European-Finnish (FIN) AF: 0.0000986 AC: 2 AN: 20282

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 2268

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 427180

Other (OTH) AF: 0.00 AC: 0 AN: 29750

GnomAD4 genome Cov.: 11

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.66
CADD	Benign	1.9
DANN	Benign	0.26
PhyloP100		-1.4
Mutation Taster		=99/1	polymorphism

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: rs763783436; hg19: chr2-152464060;