rs201971223

Variant names:

• chr2-151565051-T-C
• rs201971223
• NM_001164507.2:c.18464A>G

Your query was ambiguous. Multiple possible variants found:

• chr2-151565051-T-C
• chr2-151565051-T-G

Variant summary

Our verdict is Uncertain significance. The variant received 2 ACMG points: 2P and 0B. PM2

The NM_001164507.2(NEB):​c.18464A>G​(p.Tyr6155Cys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000213 in 1,405,968 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. Y6155S) has been classified as Likely benign.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000021 (0 hom.)
• Consequence: NEB NM_001164507.2 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 2.72
• 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: Uncertain_significance. The variant received 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
NEB	NM_001164507.2	c.18464A>G	p.Tyr6155Cys	missense_variant	Exon 117 of 182	ENST00000427231.7	NP_001157979.2
NEB	NM_001164508.2	c.18464A>G	p.Tyr6155Cys	missense_variant	Exon 117 of 182	ENST00000397345.8	NP_001157980.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
NEB	ENST00000397345.8	c.18464A>G	p.Tyr6155Cys	missense_variant	Exon 117 of 182	5	NM_001164508.2	ENSP00000380505.3
NEB	ENST00000427231.7	c.18464A>G	p.Tyr6155Cys	missense_variant	Exon 117 of 182	5	NM_001164507.2	ENSP00000416578.2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000213 AC: 3 AN: 1405968 Hom.: 0 Cov.: 27 AF XY: 0.00000285 AC XY: 2 AN XY: 701478

African (AFR) AF: 0.00 AC: 0 AN: 32244

American (AMR) AF: 0.00 AC: 0 AN: 43822

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25640

East Asian (EAS) AF: 0.0000255 AC: 1 AN: 39248

South Asian (SAS) AF: 0.00 AC: 0 AN: 82952

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 52890

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5654

European-Non Finnish (NFE) AF: 0.00000188 AC: 2 AN: 1065052

Other (OTH) AF: 0.00 AC: 0 AN: 58466

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

Inborn genetic diseases Uncertain:1

Dec 25, 2024

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.13361A>G (p.Y4454C) alteration is located in exon 90 (coding exon 88) of the NEB gene. This alteration results from a A to G substitution at nucleotide position 13361, causing the tyrosine (Y) at amino acid position 4454 to be replaced by a cysteine (C). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.24
BayesDel_addAF	Uncertain	0.046	T
BayesDel_noAF	Benign	-0.17
CADD	Uncertain	24
DANN	Uncertain	1.0
DEOGEN2	Benign	0.090	.;.;T;.;D;T;.;.
Eigen	Uncertain	0.53
Eigen_PC	Uncertain	0.55
FATHMM_MKL	Uncertain	0.81	D
LIST_S2	Uncertain	0.95	D;D;D;D;D;D;.;.
M_CAP	Benign	0.084	D
MetaRNN	Uncertain	0.55	D;D;D;D;D;D;D;D
MetaSVM	Benign	-0.66	T
MutationAssessor	Benign	1.7	L;.;.;.;L;.;.;.
PhyloP100		2.7
PrimateAI	Uncertain	0.60	T
PROVEAN	Uncertain	-3.1	D;D;.;D;D;D;.;.
REVEL	Benign	0.27
Sift	Uncertain	0.013	D;D;.;D;D;D;.;.
Sift4G	Uncertain	0.012	D;D;D;D;D;D;D;D
Polyphen		0.85	.;.;.;.;P;.;.;.
Vest4		0.60
MutPred		0.68		Loss of phosphorylation at Y4454 (P = 0.0302);.;.;.;Loss of phosphorylation at Y4454 (P = 0.0302);.;.;.;
MVP		0.62
MPC		0.36
ClinPred		0.93	D
GERP RS		6.0
Varity_R		0.12
gMVP		0.43
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: rs201971223; hg19: chr2-152421565;