2-151525940-C-G

Variant names:

• chr2-151525940-C-G
• rs6721666
• NM_001164507.2:c.22161+18G>C

Variant summary

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

The NM_001271208.2(NEB):​c.22266+18G>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.612 in 1,588,490 control chromosomes in the GnomAD database, including 300,328 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.59 (27116 hom., cov: 33)
  • Exomes 𝑓: 0.61 (273212 hom.)
• Consequence: NEB NM_001271208.2 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:8
• Conservation: PhyloP100: -1.69
• Publications: 10 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=-0.84).
• BP6: Variant 2-151525940-C-G is Benign according to our data. Variant chr2-151525940-C-G is described in ClinVar as Benign. ClinVar VariationId is 95116.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AMR) allele frequency at 95% confidence interval = 0.686 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001271208.2. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	NEB	NM_001164507.2	MANE Plus Clinical	c.22161+18G>C		intron	N/A	NP_001157979.2
	NEB	NM_001164508.2	MANE Select	c.22161+18G>C		intron	N/A	NP_001157980.2
	NEB	NM_001271208.2		c.22266+18G>C		intron	N/A	NP_001258137.2

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	NEB	ENST00000397345.8	TSL:5 MANE Select	c.22161+18G>C		intron	N/A	ENSP00000380505.3
	NEB	ENST00000427231.7	TSL:5 MANE Plus Clinical	c.22161+18G>C		intron	N/A	ENSP00000416578.2
	NEB	ENST00000409198.5	TSL:5	c.17058+18G>C		intron	N/A	ENSP00000386259.1

Frequencies

GnomAD3 genomes AF: 0.593 AC: 90096 AN: 152010 Hom.: 27090 Cov.: 33

Gnomad AFR AF: 0.514

Gnomad AMI AF: 0.507

Gnomad AMR AF: 0.697

Gnomad ASJ AF: 0.512

Gnomad EAS AF: 0.592

Gnomad SAS AF: 0.434

Gnomad FIN AF: 0.644

Gnomad MID AF: 0.662

Gnomad NFE AF: 0.626

Gnomad OTH AF: 0.588

GnomAD2 exomes AF: 0.603 AC: 150066 AN: 248986 AF XY: 0.592

Gnomad AFR exome AF: 0.516

Gnomad AMR exome AF: 0.732

Gnomad ASJ exome AF: 0.525

Gnomad EAS exome AF: 0.590

Gnomad FIN exome AF: 0.640

Gnomad NFE exome AF: 0.621

Gnomad OTH exome AF: 0.619

GnomAD4 exome AF: 0.614 AC: 881395 AN: 1436360 Hom.: 273212 Cov.: 27 AF XY: 0.608 AC XY: 435211 AN XY: 716194

African (AFR) AF: 0.516 AC: 17003 AN: 32940

American (AMR) AF: 0.724 AC: 32347 AN: 44696

Ashkenazi Jewish (ASJ) AF: 0.521 AC: 13541 AN: 25978

East Asian (EAS) AF: 0.634 AC: 25075 AN: 39576

South Asian (SAS) AF: 0.438 AC: 37554 AN: 85728

European-Finnish (FIN) AF: 0.641 AC: 34236 AN: 53396

Middle Eastern (MID) AF: 0.609 AC: 3454 AN: 5668

European-Non Finnish (NFE) AF: 0.627 AC: 682293 AN: 1088874

Other (OTH) AF: 0.603 AC: 35892 AN: 59504

GnomAD4 genome AF: 0.593 AC: 90165 AN: 152130 Hom.: 27116 Cov.: 33 AF XY: 0.594 AC XY: 44183 AN XY: 74388

African (AFR) AF: 0.514 AC: 21330 AN: 41486

American (AMR) AF: 0.697 AC: 10659 AN: 15292

Ashkenazi Jewish (ASJ) AF: 0.512 AC: 1774 AN: 3468

East Asian (EAS) AF: 0.592 AC: 3064 AN: 5176

South Asian (SAS) AF: 0.435 AC: 2091 AN: 4810

European-Finnish (FIN) AF: 0.644 AC: 6817 AN: 10588

Middle Eastern (MID) AF: 0.658 AC: 192 AN: 292

European-Non Finnish (NFE) AF: 0.626 AC: 42546 AN: 67994

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

Alfa AF: 0.549 Hom.: 2977

Bravo AF: 0.598

Asia WGS AF: 0.490 AC: 1707 AN: 3478

ClinVar

ClinVar submissions as Germline

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

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

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.84
CADD	Benign	0.52
DANN	Benign	0.27
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: rs6721666; hg19: chr2-152382454; COSMIC: COSV50839111; COSMIC: COSV50839111;