2-151697580-G-C

Position:

• chr2-151697580-G-C

Variant summary

Our verdict is Likely benign. Variant got -1 ACMG points: 2P and 3B. PM2 BP4 BP6_Moderate

The NM_001164507.2(NEB):​c.1221C>G​(p.Phe407Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000186 in 1,613,256 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 12/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★).

• Frequency:
  • Genomes: 𝑓 0.000013 (0 hom., cov: 33)
  • Exomes 𝑓: 6.8e-7 (0 hom.)
• Consequence: NEB NM_001164507.2 missense
• Clinical Significance: Likely benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 0.642

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 Likely_benign. Variant got -1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.3176449).
• BP6: Variant 2-151697580-G-C is Benign according to our data. Variant chr2-151697580-G-C is described in ClinVar as [Likely_benign]. Clinvar id is 533963.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
NEB	NM_001164507.2	c.1221C>G	p.Phe407Leu	missense_variant	14/182	ENST00000427231.7	NP_001157979.2
NEB	NM_001164508.2	c.1221C>G	p.Phe407Leu	missense_variant	14/182	ENST00000397345.8	NP_001157980.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
NEB	ENST00000397345.8	c.1221C>G	p.Phe407Leu	missense_variant	14/182	5	NM_001164508.2	ENSP00000380505	P5
NEB	ENST00000427231.7	c.1221C>G	p.Phe407Leu	missense_variant	14/182	5	NM_001164507.2	ENSP00000416578	A2
NEB	ENST00000489048.1	n.120C>G		non_coding_transcript_exon_variant	2/12	1
NEB	ENST00000409198.5	c.1221C>G	p.Phe407Leu	missense_variant	14/150	5		ENSP00000386259

Frequencies

GnomAD3 genomes AF: 0.0000131 AC: 2 AN: 152148 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.0000483

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

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

GnomAD4 exome AF: 6.84e-7 AC: 1 AN: 1461108 Hom.: 0 Cov.: 31 AF XY: 0.00000138 AC XY: 1 AN XY: 726850

Gnomad4 AFR exome AF: 0.00

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: 0.00

GnomAD4 genome AF: 0.0000131 AC: 2 AN: 152148 Hom.: 0 Cov.: 33 AF XY: 0.0000135 AC XY: 1 AN XY: 74318

Gnomad4 AFR AF: 0.0000483

Gnomad4 AMR AF: 0.00

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

Bravo AF: 0.00000378

ClinVar

Significance: Likely benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

Nemaline myopathy 2 Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Jun 20, 2022

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.92
BayesDel_addAF	Benign	-0.17	T
BayesDel_noAF	Benign	-0.48
CADD	Benign	11
DANN	Benign	0.95
DEOGEN2	Benign	0.12	.;.;T;.;T;.;.
Eigen	Benign	-0.90
Eigen_PC	Benign	-0.93
FATHMM_MKL	Uncertain	0.77	D
LIST_S2	Uncertain	0.91	D;D;D;D;D;.;.
M_CAP	Benign	0.031	D
MetaRNN	Benign	0.32	T;T;T;T;T;T;T
MetaSVM	Benign	-1.0	T
MutationAssessor	Uncertain	2.4	M;M;.;M;M;M;M
MutationTaster	Benign	1.0	N;N;N;N
PrimateAI	Uncertain	0.78	T
PROVEAN	Benign	-2.0	N;N;.;N;N;.;.
REVEL	Benign	0.23
Sift	Benign	0.37	T;T;.;T;T;.;.
Sift4G	Uncertain	0.0040	D;D;D;D;D;D;D
Polyphen		0.25	.;.;.;.;B;.;.
Vest4		0.74
MutPred		0.41		Loss of methylation at K406 (P = 0.0479);Loss of methylation at K406 (P = 0.0479);Loss of methylation at K406 (P = 0.0479);Loss of methylation at K406 (P = 0.0479);Loss of methylation at K406 (P = 0.0479);Loss of methylation at K406 (P = 0.0479);Loss of methylation at K406 (P = 0.0479);
MVP		0.13
MPC		0.27
ClinPred		0.75	D
GERP RS		-6.0
Varity_R		0.13
gMVP		0.19

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: rs1033938609; hg19: chr2-152554094;