rs368270996

Positions:

• chr2-151665397-A-G

Variant summary

Our verdict is Uncertain significance. Variant got 1 ACMG points: 3P and 2B. PM2 PP3 BP6_Moderate

The NM_001164507.2(NEB):​c.5174T>C​(p.Phe1725Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000992 in 1,613,124 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Likely benign (★).

• Frequency:
  • Genomes: 𝑓 0.000040 (0 hom., cov: 32)
  • Exomes 𝑓: 0.0000068 (0 hom.)
• Consequence: NEB NM_001164507.2 missense
• Clinical Significance: Likely benign criteria provided, single submitter U:1 B:1
• Conservation: PhyloP100: 2.85

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]

ACMG classification

Verdict is Uncertain_significance. Variant got 1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.765
• BP6: Variant 2-151665397-A-G is Benign according to our data. Variant chr2-151665397-A-G is described in ClinVar as [Likely_benign]. Clinvar id is 577311.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
NEB	NM_001164507.2	c.5174T>C	p.Phe1725Ser	missense_variant	42/182	ENST00000427231.7
NEB	NM_001164508.2	c.5174T>C	p.Phe1725Ser	missense_variant	42/182	ENST00000397345.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
NEB	ENST00000397345.8	c.5174T>C	p.Phe1725Ser	missense_variant	42/182	5	NM_001164508.2	P5
NEB	ENST00000427231.7	c.5174T>C	p.Phe1725Ser	missense_variant	42/182	5	NM_001164507.2	A2
NEB	ENST00000409198.5	c.5174T>C	p.Phe1725Ser	missense_variant	42/150	5

Frequencies

GnomAD3 genomes AF: 0.0000396 AC: 6 AN: 151530 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.000121

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0000657

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.0000201 AC: 5 AN: 249132 Hom.: 0 AF XY: 0.0000148 AC XY: 2 AN XY: 135144

Gnomad AFR exome AF: 0.000194

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00000885

Gnomad OTH exome AF: 0.000165

GnomAD4 exome AF: 0.00000684 AC: 10 AN: 1461594 Hom.: 0 Cov.: 31 AF XY: 0.00000688 AC XY: 5 AN XY: 727082

Gnomad4 AFR exome AF: 0.000239

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 8.99e-7

Gnomad4 OTH exome AF: 0.0000166

GnomAD4 genome AF: 0.0000396 AC: 6 AN: 151530 Hom.: 0 Cov.: 32 AF XY: 0.0000270 AC XY: 2 AN XY: 73956

Gnomad4 AFR AF: 0.000121

Gnomad4 AMR AF: 0.0000657

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.00

Gnomad4 OTH AF: 0.00

Alfa AF: 0.0000712 Hom.: 0

Bravo AF: 0.0000604

ESP6500AA AF: 0.000242 AC: 1

ESP6500EA AF: 0.00 AC: 0

ExAC AF: 0.0000165 AC: 2

ClinVar

Significance: Likely benign

Submissions summary: Uncertain:1 Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

Nemaline myopathy 2 Uncertain:1 Benign:1

Likely benign, criteria provided, single submitter	clinical testing	Invitae	Sep 17, 2023	- -
Uncertain significance, no assertion criteria provided	clinical testing	Natera, Inc.	Nov 11, 2019	- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.59
BayesDel_addAF	Benign	-0.16	T
BayesDel_noAF	Benign	-0.18
CADD	Benign	23
DANN	Uncertain	1.0
Eigen	Uncertain	0.48
Eigen_PC	Uncertain	0.42
FATHMM_MKL	Uncertain	0.94	D
LIST_S2	Uncertain	0.88	D;D;D;D;D;.;.
M_CAP	Benign	0.049	D
MetaRNN	Pathogenic	0.77	D;D;D;D;D;D;D
MetaSVM	Benign	-1.1	T
MutationAssessor	Pathogenic	3.1	M;M;.;M;M;M;M
MutationTaster	Benign	1.0	D;D;D;D
PrimateAI	Uncertain	0.77	T
PROVEAN	Uncertain	-3.5	D;D;.;D;D;.;.
REVEL	Benign	0.25
Sift	Uncertain	0.0090	D;T;.;T;D;.;.
Sift4G	Pathogenic	0.0	D;D;D;D;D;D;D
Polyphen		0.97	.;.;.;.;D;.;.
Vest4		0.78
MVP		0.52
MPC		0.33
ClinPred		0.65	D
GERP RS		5.0
Varity_R		0.44
gMVP		0.63

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

Publications

LitVar

Other links and lift over

dbSNP: rs368270996; hg19: chr2-152521911;