chr2-151531039-T-C

Variant names:

• chr2-151531039-T-C
• rs4664475
• NM_001164507.2:c.21585A>G

Variant summary

Our verdict is Benign. The variant received -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BA1

The NM_001164508.2(NEB):​c.21585A>G​(p.Thr7195Thr) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.603 in 1,611,460 control chromosomes in the GnomAD database, including 297,798 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.56 (24444 hom., cov: 31)
  • Exomes 𝑓: 0.61 (273354 hom.)
• Consequence: NEB NM_001164508.2 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:13
• Conservation: PhyloP100: -3.29
• Publications: 19 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 -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.86).
• BP6: Variant 2-151531039-T-C is Benign according to our data. Variant chr2-151531039-T-C is described in ClinVar as Benign. ClinVar VariationId is 95114.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=-3.29 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (AMR) allele frequency at 95% confidence interval = 0.671 is higher than 0.05.

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.21585A>G	p.Thr7195Thr	synonymous	Exon 145 of 182	NP_001157979.2	P20929-3
	NEB	NM_001164508.2	MANE Select	c.21585A>G	p.Thr7195Thr	synonymous	Exon 145 of 182	NP_001157980.2	P20929-2
	NEB	NM_001271208.2		c.21690A>G	p.Thr7230Thr	synonymous	Exon 146 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.21585A>G	p.Thr7195Thr	synonymous	Exon 145 of 182	ENSP00000380505.3	P20929-2
	NEB	ENST00000427231.7	TSL:5 MANE Plus Clinical	c.21585A>G	p.Thr7195Thr	synonymous	Exon 145 of 182	ENSP00000416578.2	P20929-3
	NEB	ENST00000409198.5	TSL:5	c.16482A>G	p.Thr5494Thr	synonymous	Exon 118 of 150	ENSP00000386259.1	P20929-4

Frequencies

GnomAD3 genomes AF: 0.555 AC: 84284 AN: 151820 Hom.: 24422 Cov.: 31

Gnomad AFR AF: 0.389

Gnomad AMI AF: 0.509

Gnomad AMR AF: 0.681

Gnomad ASJ AF: 0.510

Gnomad EAS AF: 0.582

Gnomad SAS AF: 0.403

Gnomad FIN AF: 0.644

Gnomad MID AF: 0.649

Gnomad NFE AF: 0.625

Gnomad OTH AF: 0.565

GnomAD2 exomes AF: 0.589 AC: 145970 AN: 247906 AF XY: 0.579

Gnomad AFR exome AF: 0.389

Gnomad AMR exome AF: 0.724

Gnomad ASJ exome AF: 0.523

Gnomad EAS exome AF: 0.578

Gnomad FIN exome AF: 0.639

Gnomad NFE exome AF: 0.620

Gnomad OTH exome AF: 0.610

GnomAD4 exome AF: 0.608 AC: 886922 AN: 1459522 Hom.: 273354 Cov.: 39 AF XY: 0.601 AC XY: 436676 AN XY: 726030

African (AFR) AF: 0.387 AC: 12933 AN: 33448

American (AMR) AF: 0.716 AC: 31948 AN: 44620

Ashkenazi Jewish (ASJ) AF: 0.520 AC: 13575 AN: 26116

East Asian (EAS) AF: 0.626 AC: 24832 AN: 39648

South Asian (SAS) AF: 0.410 AC: 35327 AN: 86088

European-Finnish (FIN) AF: 0.641 AC: 34202 AN: 53370

Middle Eastern (MID) AF: 0.602 AC: 3474 AN: 5766

European-Non Finnish (NFE) AF: 0.626 AC: 695049 AN: 1110194

Other (OTH) AF: 0.590 AC: 35582 AN: 60272

GnomAD4 genome AF: 0.555 AC: 84339 AN: 151938 Hom.: 24444 Cov.: 31 AF XY: 0.557 AC XY: 41374 AN XY: 74264

African (AFR) AF: 0.390 AC: 16118 AN: 41378

American (AMR) AF: 0.682 AC: 10407 AN: 15264

Ashkenazi Jewish (ASJ) AF: 0.510 AC: 1770 AN: 3472

East Asian (EAS) AF: 0.582 AC: 3014 AN: 5178

South Asian (SAS) AF: 0.404 AC: 1942 AN: 4810

European-Finnish (FIN) AF: 0.644 AC: 6795 AN: 10556

Middle Eastern (MID) AF: 0.646 AC: 190 AN: 294

European-Non Finnish (NFE) AF: 0.625 AC: 42462 AN: 67966

Other (OTH) AF: 0.558 AC: 1178 AN: 2110

Alfa AF: 0.600 Hom.: 42917

Bravo AF: 0.556

Asia WGS AF: 0.451 AC: 1572 AN: 3478

EpiCase AF: 0.602

EpiControl AF: 0.612

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	5	not specified (5)
-	-	4	Nemaline myopathy 2 (4)
-	-	3	not provided (3)
-	-	1	Arthrogryposis multiplex congenita 6 (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.86
CADD	Benign	0.094
DANN	Benign	0.53
PhyloP100		-3.3
Mutation Taster		=89/11	polymorphism (auto)

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: rs4664475; hg19: chr2-152387553; COSMIC: COSV51424628; COSMIC: COSV51424628;