rs16830136

Variant names:

• chr2-151518286-G-A
• rs16830136
• NM_001164507.2:c.22800+32C>T

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_001164508.2(NEB):​c.22800+32C>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.609 in 1,451,234 control chromosomes in the GnomAD database, including 272,464 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.59 (26967 hom., cov: 32)
  • Exomes 𝑓: 0.61 (245497 hom.)
• Consequence: NEB NM_001164508.2 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:4
• Conservation: PhyloP100: -1.74
• Publications: 8 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 (BayesDel_noAF=-0.87).
• BP6: Variant 2-151518286-G-A is Benign according to our data. Variant chr2-151518286-G-A is described in ClinVar as Benign. ClinVar VariationId is 257792.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AMR) allele frequency at 95% confidence interval = 0.685 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.22800+32C>T		intron	N/A	NP_001157979.2	P20929-3
	NEB	NM_001164508.2	MANE Select	c.22800+32C>T		intron	N/A	NP_001157980.2	P20929-2
	NEB	NM_001271208.2		c.22905+32C>T		intron	N/A	NP_001258137.2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	NEB	ENST00000397345.8	TSL:5 MANE Select	c.22800+32C>T		intron	N/A	ENSP00000380505.3	P20929-2
	NEB	ENST00000427231.7	TSL:5 MANE Plus Clinical	c.22800+32C>T		intron	N/A	ENSP00000416578.2	P20929-3
	NEB	ENST00000409198.5	TSL:5	c.17697+32C>T		intron	N/A	ENSP00000386259.1	P20929-4

Frequencies

GnomAD3 genomes AF: 0.591 AC: 89787 AN: 151888 Hom.: 26944 Cov.: 32

Gnomad AFR AF: 0.514

Gnomad AMI AF: 0.508

Gnomad AMR AF: 0.695

Gnomad ASJ AF: 0.511

Gnomad EAS AF: 0.583

Gnomad SAS AF: 0.404

Gnomad FIN AF: 0.643

Gnomad MID AF: 0.658

Gnomad NFE AF: 0.625

Gnomad OTH AF: 0.588

GnomAD2 exomes AF: 0.598 AC: 148937 AN: 248920 AF XY: 0.586

Gnomad AFR exome AF: 0.516

Gnomad AMR exome AF: 0.732

Gnomad ASJ exome AF: 0.525

Gnomad EAS exome AF: 0.580

Gnomad FIN exome AF: 0.640

Gnomad NFE exome AF: 0.621

Gnomad OTH exome AF: 0.616

GnomAD4 exome AF: 0.611 AC: 793734 AN: 1299228 Hom.: 245497 Cov.: 20 AF XY: 0.604 AC XY: 395239 AN XY: 654820

African (AFR) AF: 0.519 AC: 15569 AN: 30016

American (AMR) AF: 0.724 AC: 32204 AN: 44508

Ashkenazi Jewish (ASJ) AF: 0.521 AC: 13090 AN: 25136

East Asian (EAS) AF: 0.628 AC: 24403 AN: 38880

South Asian (SAS) AF: 0.412 AC: 34151 AN: 82940

European-Finnish (FIN) AF: 0.641 AC: 34170 AN: 53310

Middle Eastern (MID) AF: 0.610 AC: 3322 AN: 5444

European-Non Finnish (NFE) AF: 0.626 AC: 603818 AN: 964038

Other (OTH) AF: 0.601 AC: 33007 AN: 54956

GnomAD4 genome AF: 0.591 AC: 89850 AN: 152006 Hom.: 26967 Cov.: 32 AF XY: 0.592 AC XY: 43978 AN XY: 74304

African (AFR) AF: 0.514 AC: 21309 AN: 41442

American (AMR) AF: 0.696 AC: 10629 AN: 15272

Ashkenazi Jewish (ASJ) AF: 0.511 AC: 1772 AN: 3470

East Asian (EAS) AF: 0.583 AC: 3009 AN: 5164

South Asian (SAS) AF: 0.404 AC: 1943 AN: 4810

European-Finnish (FIN) AF: 0.643 AC: 6791 AN: 10556

Middle Eastern (MID) AF: 0.653 AC: 192 AN: 294

European-Non Finnish (NFE) AF: 0.625 AC: 42511 AN: 67972

Other (OTH) AF: 0.582 AC: 1231 AN: 2114

Alfa AF: 0.608 Hom.: 5355

Bravo AF: 0.597

Asia WGS AF: 0.463 AC: 1613 AN: 3478

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	1	Arthrogryposis multiplex congenita 6 (1)
-	-	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_noAF	Benign	-0.87
CADD	Benign	0.021
DANN	Benign	0.47
PhyloP100		-1.7
Mutation Taster		=100/0	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: rs16830136; hg19: chr2-152374800; COSMIC: COSV51437777; COSMIC: COSV51437777;