rs200963111

Variant names:

• chr2-151513680-C-T
• rs200963111
• NM_001164507.2:c.23141G>A

Your query was ambiguous. Multiple possible variants found:

• chr2-151513680-C-T
• chr2-151513680-C-G

Variant summary

Our verdict is Benign. The variant received -9 ACMG points: 0P and 9B. BP4_Strong BP6 BS1

The NM_001164508.2(NEB):​c.23141G>A​(p.Arg7714Gln) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000133 in 1,599,716 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 14/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.00063 (0 hom., cov: 32)
  • Exomes 𝑓: 0.000080 (0 hom.)
• Consequence: NEB NM_001164508.2 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:3 B:4
• Conservation: PhyloP100: 2.39
• 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

Our verdict: Benign. The variant received -9 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.01810959).
• BP6: Variant 2-151513680-C-T is Benign according to our data. Variant chr2-151513680-C-T is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 257796.
• BS1: Variant frequency is greater than expected in population afr. GnomAdExome4 allele frequency = 0.0000801 (116/1447796) while in subpopulation AFR AF = 0.00249 (83/33338). AF 95% confidence interval is 0.00206. There are 0 homozygotes in GnomAdExome4. There are 42 alleles in the male GnomAdExome4 subpopulation. Median coverage is 30. This position passed quality control check.

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.23141G>A	p.Arg7714Gln	missense	Exon 160 of 182	NP_001157979.2	P20929-3
	NEB	NM_001164508.2	MANE Select	c.23141G>A	p.Arg7714Gln	missense	Exon 160 of 182	NP_001157980.2	P20929-2
	NEB	NM_001271208.2		c.23246G>A	p.Arg7749Gln	missense	Exon 161 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.23141G>A	p.Arg7714Gln	missense	Exon 160 of 182	ENSP00000380505.3	P20929-2
	NEB	ENST00000427231.7	TSL:5 MANE Plus Clinical	c.23141G>A	p.Arg7714Gln	missense	Exon 160 of 182	ENSP00000416578.2	P20929-3
	NEB	ENST00000409198.5	TSL:5	c.18038G>A	p.Arg6013Gln	missense	Exon 133 of 150	ENSP00000386259.1	P20929-4

Frequencies

GnomAD3 genomes AF: 0.000619 AC: 94 AN: 151804 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.00220

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: 0.0000294

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.000142 AC: 32 AN: 225430 AF XY: 0.0000906

Gnomad AFR exome AF: 0.00184

Gnomad AMR exome AF: 0.0000622

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.000242

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000801 AC: 116 AN: 1447796 Hom.: 0 Cov.: 30 AF XY: 0.0000584 AC XY: 42 AN XY: 718666

African (AFR) AF: 0.00249 AC: 83 AN: 33338

American (AMR) AF: 0.0000232 AC: 1 AN: 43118

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25842

East Asian (EAS) AF: 0.000177 AC: 7 AN: 39476

South Asian (SAS) AF: 0.00 AC: 0 AN: 83550

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 52728

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5744

European-Non Finnish (NFE) AF: 0.0000154 AC: 17 AN: 1104080

Other (OTH) AF: 0.000134 AC: 8 AN: 59920

GnomAD4 genome AF: 0.000632 AC: 96 AN: 151920 Hom.: 0 Cov.: 32 AF XY: 0.000539 AC XY: 40 AN XY: 74218

African (AFR) AF: 0.00225 AC: 93 AN: 41404

American (AMR) AF: 0.0000656 AC: 1 AN: 15252

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5180

South Asian (SAS) AF: 0.00 AC: 0 AN: 4796

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10512

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

European-Non Finnish (NFE) AF: 0.0000294 AC: 2 AN: 67988

Other (OTH) AF: 0.00 AC: 0 AN: 2112

Alfa AF: 0.000218 Hom.: 0

Bravo AF: 0.000688

ESP6500AA AF: 0.00160 AC: 6

ESP6500EA AF: 0.000122 AC: 1

ExAC AF: 0.000174 AC: 21

ClinVar

ClinVar submissions

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
-	1	1	Nemaline myopathy 2 (2)
-	1	1	not provided (2)
-	-	2	not specified (2)
-	1	-	Inborn genetic diseases (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.13
BayesDel_addAF	Benign	-0.44	T
BayesDel_noAF	Benign	-0.41
CADD	Benign	23
DANN	Uncertain	1.0
DEOGEN2	Benign	0.019	T
Eigen	Uncertain	0.35
Eigen_PC	Uncertain	0.37
FATHMM_MKL	Benign	0.68	D
LIST_S2	Benign	0.82	T
M_CAP	Benign	0.033	D
MetaRNN	Benign	0.018	T
MetaSVM	Benign	-0.99	T
MutationAssessor	Benign	1.2	L
PhyloP100		2.4
PrimateAI	Benign	0.43	T
PROVEAN	Benign	-1.1	N
REVEL	Benign	0.094
Sift	Benign	0.18	T
Sift4G	Uncertain	0.0090	D
Polyphen		0.99	D
Vest4		0.29
MVP		0.56
MPC		0.26
ClinPred		0.069	T
GERP RS		4.5
PromoterAI		-0.019	Neutral
Varity_R		0.11
gMVP		0.052
Mutation Taster		=92/8	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: rs200963111; hg19: chr2-152370194; COSMIC: COSV51436913; COSMIC: COSV51436913;