rs13031275

Variant names:

• chr2-151489980-A-C
• rs13031275
• NM_001164507.2:c.25395T>G

Your query was ambiguous. Multiple possible variants found:

• chr2-151489980-A-C
• chr2-151489980-A-G

Variant summary

Our verdict is Benign. The variant received -19 ACMG points: 0P and 19B. BP4_Moderate BP6_Very_Strong BP7 BA1

The NM_001164508.2(NEB):​c.25395T>G​(p.Ser8465Ser) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0544 in 1,590,030 control chromosomes in the GnomAD database, including 2,772 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.038 (154 hom., cov: 32)
  • Exomes 𝑓: 0.056 (2618 hom.)
• Consequence: NEB NM_001164508.2 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:9
• Conservation: PhyloP100: -0.804
• Publications: 9 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 -19 ACMG points.

• BP4: Computational evidence support a benign effect (REVEL=0.04).
• BP6: Variant 2-151489980-A-C is Benign according to our data. Variant chr2-151489980-A-C is described in ClinVar as Benign. ClinVar VariationId is 129735.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=-0.804 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.0592 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.25395T>G	p.Ser8465Ser	synonymous	Exon 181 of 182	NP_001157979.2	P20929-3
	NEB	NM_001164508.2	MANE Select	c.25395T>G	p.Ser8465Ser	synonymous	Exon 181 of 182	NP_001157980.2	P20929-2
	NEB	NM_001271208.2		c.25500T>G	p.Ser8500Ser	synonymous	Exon 182 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.25395T>G	p.Ser8465Ser	synonymous	Exon 181 of 182	ENSP00000380505.3	P20929-2
	NEB	ENST00000427231.7	TSL:5 MANE Plus Clinical	c.25395T>G	p.Ser8465Ser	synonymous	Exon 181 of 182	ENSP00000416578.2	P20929-3
	RIF1	ENST00000457745.1	TSL:1	n.480+3224A>C		intron	N/A

Frequencies

GnomAD3 genomes AF: 0.0379 AC: 5775 AN: 152176 Hom.: 154 Cov.: 32

Gnomad AFR AF: 0.0119

Gnomad AMI AF: 0.0921

Gnomad AMR AF: 0.0268

Gnomad ASJ AF: 0.0493

Gnomad EAS AF: 0.000192

Gnomad SAS AF: 0.0176

Gnomad FIN AF: 0.0287

Gnomad MID AF: 0.0475

Gnomad NFE AF: 0.0607

Gnomad OTH AF: 0.0373

GnomAD2 exomes AF: 0.0418 AC: 10392 AN: 248880 AF XY: 0.0425

Gnomad AFR exome AF: 0.0120

Gnomad AMR exome AF: 0.0217

Gnomad ASJ exome AF: 0.0451

Gnomad EAS exome AF: 0.0000557

Gnomad FIN exome AF: 0.0311

Gnomad NFE exome AF: 0.0657

Gnomad OTH exome AF: 0.0437

GnomAD4 exome AF: 0.0561 AC: 80722 AN: 1437736 Hom.: 2618 Cov.: 29 AF XY: 0.0554 AC XY: 39726 AN XY: 716786

African (AFR) AF: 0.00966 AC: 318 AN: 32914

American (AMR) AF: 0.0232 AC: 1038 AN: 44688

Ashkenazi Jewish (ASJ) AF: 0.0458 AC: 1191 AN: 26016

East Asian (EAS) AF: 0.0000758 AC: 3 AN: 39576

South Asian (SAS) AF: 0.0219 AC: 1874 AN: 85754

European-Finnish (FIN) AF: 0.0336 AC: 1796 AN: 53378

Middle Eastern (MID) AF: 0.0353 AC: 202 AN: 5724

European-Non Finnish (NFE) AF: 0.0657 AC: 71583 AN: 1090104

Other (OTH) AF: 0.0456 AC: 2717 AN: 59582

GnomAD4 genome AF: 0.0379 AC: 5772 AN: 152294 Hom.: 154 Cov.: 32 AF XY: 0.0352 AC XY: 2621 AN XY: 74474

African (AFR) AF: 0.0119 AC: 495 AN: 41566

American (AMR) AF: 0.0267 AC: 409 AN: 15298

Ashkenazi Jewish (ASJ) AF: 0.0493 AC: 171 AN: 3468

East Asian (EAS) AF: 0.000193 AC: 1 AN: 5184

South Asian (SAS) AF: 0.0174 AC: 84 AN: 4828

European-Finnish (FIN) AF: 0.0287 AC: 305 AN: 10610

Middle Eastern (MID) AF: 0.0476 AC: 14 AN: 294

European-Non Finnish (NFE) AF: 0.0607 AC: 4131 AN: 68020

Other (OTH) AF: 0.0369 AC: 78 AN: 2114

Alfa AF: 0.0566 Hom.: 891

Bravo AF: 0.0375

Asia WGS AF: 0.00953 AC: 34 AN: 3478

EpiCase AF: 0.0599

EpiControl AF: 0.0622

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	5	not specified (5)
-	-	3	Nemaline myopathy 2 (3)
-	-	1	not provided (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.53
CADD	Benign	1.9
DANN	Benign	0.75
PhyloP100		-0.80
Mutation Taster		=96/4	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: rs13031275; hg19: chr2-152346494;