rs189655274

Variant names:

• chr2-151499356-G-A
• rs189655274
• NM_001164507.2:c.24056C>T

Your query was ambiguous. Multiple possible variants found:

• chr2-151499356-G-A
• chr2-151499356-G-T

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The NM_001164508.2(NEB):​c.24056C>T​(p.Pro8019Leu) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000473 in 1,546,346 control chromosomes in the GnomAD database, including 5 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0025 (2 hom., cov: 32)
  • Exomes 𝑓: 0.00025 (3 hom.)
• Consequence: NEB NM_001164508.2 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: 8.12
• Publications: 1 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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.009014547).
• BP6: Variant 2-151499356-G-A is Benign according to our data. Variant chr2-151499356-G-A is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 380238.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.00254 (387/152212) while in subpopulation AFR AF = 0.00886 (368/41542). AF 95% confidence interval is 0.00811. There are 2 homozygotes in GnomAd4. There are 171 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 2 AD,AR gene

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.24056C>T	p.Pro8019Leu	missense	Exon 169 of 182	NP_001157979.2	P20929-3
	NEB	NM_001164508.2	MANE Select	c.24056C>T	p.Pro8019Leu	missense	Exon 169 of 182	NP_001157980.2	P20929-2
	NEB	NM_001271208.2		c.24161C>T	p.Pro8054Leu	missense	Exon 170 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.24056C>T	p.Pro8019Leu	missense	Exon 169 of 182	ENSP00000380505.3	P20929-2
	NEB	ENST00000427231.7	TSL:5 MANE Plus Clinical	c.24056C>T	p.Pro8019Leu	missense	Exon 169 of 182	ENSP00000416578.2	P20929-3
	NEB	ENST00000688578.1		c.839C>T	p.Pro280Leu	missense	Exon 10 of 21	ENSP00000509628.1	A0A8I5KS37

Frequencies

GnomAD3 genomes AF: 0.00254 AC: 386 AN: 152094 Hom.: 2 Cov.: 32

Gnomad AFR AF: 0.00886

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000786

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: 0.00334

GnomAD2 exomes AF: 0.000514 AC: 80 AN: 155564 AF XY: 0.000340

Gnomad AFR exome AF: 0.00956

Gnomad AMR exome AF: 0.000123

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000165

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.000247 AC: 345 AN: 1394134 Hom.: 3 Cov.: 27 AF XY: 0.000202 AC XY: 139 AN XY: 687826

African (AFR) AF: 0.00914 AC: 287 AN: 31412

American (AMR) AF: 0.000197 AC: 7 AN: 35472

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25090

East Asian (EAS) AF: 0.00 AC: 0 AN: 35472

South Asian (SAS) AF: 0.00 AC: 0 AN: 78984

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 48682

Middle Eastern (MID) AF: 0.000176 AC: 1 AN: 5674

European-Non Finnish (NFE) AF: 0.0000130 AC: 14 AN: 1075522

Other (OTH) AF: 0.000623 AC: 36 AN: 57826

GnomAD4 genome AF: 0.00254 AC: 387 AN: 152212 Hom.: 2 Cov.: 32 AF XY: 0.00230 AC XY: 171 AN XY: 74434

African (AFR) AF: 0.00886 AC: 368 AN: 41542

American (AMR) AF: 0.000785 AC: 12 AN: 15278

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3468

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

South Asian (SAS) AF: 0.00 AC: 0 AN: 4820

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10592

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

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 68008

Other (OTH) AF: 0.00331 AC: 7 AN: 2116

Alfa AF: 0.00202 Hom.: 3

Bravo AF: 0.00301

ESP6500AA AF: 0.0123 AC: 17

ESP6500EA AF: 0.00 AC: 0

ExAC AF: 0.000760 AC: 31

Asia WGS AF: 0.000577 AC: 2 AN: 3478

ClinVar

ClinVar submissions

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

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

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Benign	-0.49	T
BayesDel_noAF	Benign	-0.46
CADD	Uncertain	24
DANN	Benign	0.96
DEOGEN2	Benign	0.042	T
Eigen	Uncertain	0.42
Eigen_PC	Uncertain	0.55
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Benign	0.76	T
MetaRNN	Benign	0.0090	T
MetaSVM	Benign	-1.0	T
PhyloP100		8.1
PROVEAN	Uncertain	-2.7	D
REVEL	Benign	0.18
Sift	Benign	0.63	T
Sift4G	Uncertain	0.046	D
Vest4		0.68
MVP		0.49
MPC		0.29
ClinPred		0.047	T
GERP RS		6.1
gMVP		0.031
Mutation Taster		=71/29	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.090		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: rs189655274; hg19: chr2-152355870;