2-151531795-G-T

Variant names:

• chr2-151531795-G-T
• rs16830170
• NM_001164507.2:c.21519C>A

Variant summary

Our verdict is Uncertain significance. The variant received 4 ACMG points: 4P and 0B. PM2 PP3_Moderate

The NM_001164508.2(NEB):​c.21519C>A​(p.Ser7173Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★). Synonymous variant affecting the same amino acid position (i.e. S7173S) has been classified as Benign. The gene NEB is included in the ClinGen Criteria Specification Registry.

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.0 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: NEB NM_001164508.2 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: -0.0580
• 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]

RIF1 (HGNC:23207): (replication timing regulatory factor 1) This gene encodes a protein that shares homology with the yeast teleomere binding protein, Rap1 interacting factor 1. This protein localizes to aberrant telomeres may be involved in DNA repair. Alternate splicing results in multiple transcript variants. [provided by RefSeq, Apr 2010]

ACMG classification

Specifications for NEB are available in the ClinGen Criteria Specification Registry and recommended for reference when assigning criteria.

Our verdict: Uncertain_significance. The variant received 4 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.936

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.21519C>A	p.Ser7173Arg	missense	Exon 144 of 182	NP_001157979.2	P20929-3
	NEB	NM_001164508.2	MANE Select	c.21519C>A	p.Ser7173Arg	missense	Exon 144 of 182	NP_001157980.2	P20929-2
	NEB	NM_001271208.2		c.21624C>A	p.Ser7208Arg	missense	Exon 145 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.21519C>A	p.Ser7173Arg	missense	Exon 144 of 182	ENSP00000380505.3	P20929-2
	NEB	ENST00000427231.7	TSL:5 MANE Plus Clinical	c.21519C>A	p.Ser7173Arg	missense	Exon 144 of 182	ENSP00000416578.2	P20929-3
	NEB	ENST00000409198.5	TSL:5	c.16416C>A	p.Ser5472Arg	missense	Exon 117 of 150	ENSP00000386259.1	P20929-4

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Data not reliable, filtered out with message: AC0 AF: 0.00 AC: 0 AN: 1454130 Hom.: 0 Cov.: 31 AF XY: 0.00 AC XY: 0 AN XY: 723386

African (AFR) AF: 0.00 AC: 0 AN: 33312

American (AMR) AF: 0.00 AC: 0 AN: 44510

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26046

East Asian (EAS) AF: 0.00 AC: 0 AN: 39616

South Asian (SAS) AF: 0.00 AC: 0 AN: 85448

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53284

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5756

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1105992

Other (OTH) AF: 0.00 AC: 0 AN: 60166

GnomAD4 genome Cov.: 33

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	Nemaline myopathy 2 (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.96
BayesDel_addAF	Pathogenic	0.36	D
BayesDel_noAF	Pathogenic	0.29
CADD	Benign	13
DANN	Uncertain	1.0
DEOGEN2	Benign	0.14	T
Eigen	Benign	0.16
Eigen_PC	Benign	0.020
FATHMM_MKL	Benign	0.48	N
LIST_S2	Uncertain	0.93	D
M_CAP	Pathogenic	0.41	D
MetaRNN	Pathogenic	0.94	D
MetaSVM	Uncertain	0.40	D
MutationAssessor	Pathogenic	3.7	H
PhyloP100		-0.058
PrimateAI	Pathogenic	0.80	T
PROVEAN	Uncertain	-2.9	D
REVEL	Pathogenic	0.85
Sift	Pathogenic	0.0	D
Sift4G	Pathogenic	0.0	D
Polyphen		1.0	D
Vest4		0.85
MutPred		0.83		Gain of MoRF binding (P = 0.0174)
MVP		0.88
MPC		0.36
ClinPred		1.0	D
GERP RS		0.91
Varity_R		0.78
gMVP		0.68
Mutation Taster		=61/39	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.020		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: rs16830170; hg19: chr2-152388309;