2-151529260-C-G

Variant names:

• chr2-151529260-C-G
• rs201979610
• NM_001164507.2:c.21685G>C

Variant summary

Our verdict is Benign. The variant received -10 ACMG points: 0P and 10B. BP4_Strong BP6 BS1 BS2_Supporting

The NM_001271208.2(NEB):​c.21790G>C​(p.Asp7264His) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00277 in 1,613,710 control chromosomes in the GnomAD database, including 4 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.0017 (0 hom., cov: 32)
  • Exomes 𝑓: 0.0029 (4 hom.)
• Consequence: NEB NM_001271208.2 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:5 B:5
• Conservation: PhyloP100: 7.91
• Publications: 3 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

Our verdict: Benign. The variant received -10 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0207026).
• BP6: Variant 2-151529260-C-G is Benign according to our data. Variant chr2-151529260-C-G is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 193961.
• BS1: Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.00172 (262/152312) while in subpopulation NFE AF = 0.00332 (226/68036). AF 95% confidence interval is 0.00297. There are 0 homozygotes in GnomAd4. There are 117 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High Homozygotes in GnomAdExome4 at 4 AD,AR geneVariant has number of homozygotes lower than other variant known as pathogenic in the gene, so the strength is limited to Supporting.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001271208.2. 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.21685G>C	p.Asp7229His	missense	Exon 146 of 182	NP_001157979.2
	NEB	NM_001164508.2	MANE Select	c.21685G>C	p.Asp7229His	missense	Exon 146 of 182	NP_001157980.2
	NEB	NM_001271208.2		c.21790G>C	p.Asp7264His	missense	Exon 147 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.21685G>C	p.Asp7229His	missense	Exon 146 of 182	ENSP00000380505.3
	NEB	ENST00000427231.7	TSL:5 MANE Plus Clinical	c.21685G>C	p.Asp7229His	missense	Exon 146 of 182	ENSP00000416578.2
	NEB	ENST00000409198.5	TSL:5	c.16582G>C	p.Asp5528His	missense	Exon 119 of 150	ENSP00000386259.1

Frequencies

GnomAD3 genomes AF: 0.00172 AC: 262 AN: 152194 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.000362

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000458

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000414

Gnomad FIN AF: 0.00104

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00332

Gnomad OTH AF: 0.000478

GnomAD2 exomes AF: 0.00183 AC: 456 AN: 249136 AF XY: 0.00186

Gnomad AFR exome AF: 0.000258

Gnomad AMR exome AF: 0.000174

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.000111

Gnomad FIN exome AF: 0.000835

Gnomad NFE exome AF: 0.00360

Gnomad OTH exome AF: 0.000827

GnomAD4 exome AF: 0.00288 AC: 4205 AN: 1461398 Hom.: 4 Cov.: 30 AF XY: 0.00285 AC XY: 2072 AN XY: 727002

African (AFR) AF: 0.000448 AC: 15 AN: 33474

American (AMR) AF: 0.000179 AC: 8 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26130

East Asian (EAS) AF: 0.0000756 AC: 3 AN: 39684

South Asian (SAS) AF: 0.000383 AC: 33 AN: 86248

European-Finnish (FIN) AF: 0.000824 AC: 44 AN: 53398

Middle Eastern (MID) AF: 0.000347 AC: 2 AN: 5766

European-Non Finnish (NFE) AF: 0.00361 AC: 4012 AN: 1111604

Other (OTH) AF: 0.00146 AC: 88 AN: 60370

GnomAD4 genome AF: 0.00172 AC: 262 AN: 152312 Hom.: 0 Cov.: 32 AF XY: 0.00157 AC XY: 117 AN XY: 74476

African (AFR) AF: 0.000361 AC: 15 AN: 41564

American (AMR) AF: 0.000457 AC: 7 AN: 15304

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5182

South Asian (SAS) AF: 0.000414 AC: 2 AN: 4828

European-Finnish (FIN) AF: 0.00104 AC: 11 AN: 10608

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.00332 AC: 226 AN: 68036

Other (OTH) AF: 0.000473 AC: 1 AN: 2112

Alfa AF: 0.00290 Hom.: 0

Bravo AF: 0.00169

TwinsUK AF: 0.00431 AC: 16

ALSPAC AF: 0.00519 AC: 20

ESP6500AA AF: 0.000260 AC: 1

ESP6500EA AF: 0.00277 AC: 23

ExAC AF: 0.00190 AC: 230

EpiCase AF: 0.00229

EpiControl AF: 0.00338

ClinVar

ClinVar submissions as Germline

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
-	4	-	not provided (4)
-	1	2	Nemaline myopathy 2 (3)
-	-	2	not specified (2)
-	-	1	NEB-related disorder (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.30
BayesDel_addAF	Benign	-0.19	T
BayesDel_noAF	Uncertain	-0.040
CADD	Uncertain	25
DANN	Uncertain	0.98
DEOGEN2	Benign	0.11	T
Eigen	Pathogenic	0.80
Eigen_PC	Pathogenic	0.82
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.92	D
M_CAP	Benign	0.062	D
MetaRNN	Benign	0.021	T
MetaSVM	Benign	-0.61	T
MutationAssessor	Uncertain	2.4	M
PhyloP100		7.9
PrimateAI	Uncertain	0.59	T
PROVEAN	Uncertain	-3.1	D
REVEL	Uncertain	0.43
Sift	Uncertain	0.0010	D
Sift4G	Pathogenic	0.0010	D
Polyphen		0.99	D
Vest4		0.60
MVP		0.71
MPC		0.36
ClinPred		0.050	T
GERP RS		5.8
Varity_R		0.49
gMVP		0.57
Mutation Taster		=50/50

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: rs201979610; hg19: chr2-152385774; COSMIC: COSV50813248; COSMIC: COSV50813248;