rs3732309

Variant names:

• chr2-151516460-C-T
• rs3732309
• NM_001164507.2:c.22904G>A

Your query was ambiguous. Multiple possible variants found:

• chr2-151516460-C-T
• chr2-151516460-C-G

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.22904G>A​(p.Gly7635Glu) variant causes a missense change. The variant allele was found at a frequency of 0.00162 in 1,605,246 control chromosomes in the GnomAD database, including 37 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/23 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Synonymous variant affecting the same amino acid position (i.e. G7635G) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.0023 (8 hom., cov: 32)
  • Exomes 𝑓: 0.0016 (29 hom.)
• Consequence: NEB NM_001164508.2 missense
• Scores: Splicing: ADA: 0.003922
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:8
• Conservation: PhyloP100: 5.02
• 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 (MetaRNN=0.005690187).
• BP6: Variant 2-151516460-C-T is Benign according to our data. Variant chr2-151516460-C-T is described in ClinVar as Benign. ClinVar VariationId is 194291.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population eas. GnomAd4 allele frequency = 0.00226 (344/152204) while in subpopulation EAS AF = 0.0444 (230/5184). AF 95% confidence interval is 0.0397. There are 8 homozygotes in GnomAd4. There are 180 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 8 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.22904G>A	p.Gly7635Glu	missense	Exon 157 of 182	NP_001157979.2	P20929-3
	NEB	NM_001164508.2	MANE Select	c.22904G>A	p.Gly7635Glu	missense	Exon 157 of 182	NP_001157980.2	P20929-2
	NEB	NM_001271208.2		c.23009G>A	p.Gly7670Glu	missense	Exon 158 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.22904G>A	p.Gly7635Glu	missense	Exon 157 of 182	ENSP00000380505.3	P20929-2
	NEB	ENST00000427231.7	TSL:5 MANE Plus Clinical	c.22904G>A	p.Gly7635Glu	missense	Exon 157 of 182	ENSP00000416578.2	P20929-3
	NEB	ENST00000409198.5	TSL:5	c.17801G>A	p.Gly5934Glu	missense	Exon 130 of 150	ENSP00000386259.1	P20929-4

Frequencies

GnomAD3 genomes AF: 0.00228 AC: 346 AN: 152086 Hom.: 8 Cov.: 32

Gnomad AFR AF: 0.000507

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00380

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.0450

Gnomad SAS AF: 0.00270

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000206

Gnomad OTH AF: 0.00287

GnomAD2 exomes AF: 0.00519 AC: 1283 AN: 247432 AF XY: 0.00477

Gnomad AFR exome AF: 0.000259

Gnomad AMR exome AF: 0.00990

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.0468

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000312

Gnomad OTH exome AF: 0.00283

GnomAD4 exome AF: 0.00155 AC: 2254 AN: 1453042 Hom.: 29 Cov.: 29 AF XY: 0.00147 AC XY: 1064 AN XY: 723208

African (AFR) AF: 0.000330 AC: 11 AN: 33302

American (AMR) AF: 0.00918 AC: 409 AN: 44558

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26032

East Asian (EAS) AF: 0.0307 AC: 1217 AN: 39604

South Asian (SAS) AF: 0.00183 AC: 157 AN: 85746

European-Finnish (FIN) AF: 0.0000375 AC: 2 AN: 53340

Middle Eastern (MID) AF: 0.000174 AC: 1 AN: 5750

European-Non Finnish (NFE) AF: 0.000201 AC: 222 AN: 1104610

Other (OTH) AF: 0.00391 AC: 235 AN: 60100

GnomAD4 genome AF: 0.00226 AC: 344 AN: 152204 Hom.: 8 Cov.: 32 AF XY: 0.00242 AC XY: 180 AN XY: 74416

African (AFR) AF: 0.000506 AC: 21 AN: 41532

American (AMR) AF: 0.00379 AC: 58 AN: 15284

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3470

East Asian (EAS) AF: 0.0444 AC: 230 AN: 5184

South Asian (SAS) AF: 0.00270 AC: 13 AN: 4806

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10608

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

European-Non Finnish (NFE) AF: 0.000206 AC: 14 AN: 68002

Other (OTH) AF: 0.00379 AC: 8 AN: 2112

Alfa AF: 0.00170 Hom.: 13

Bravo AF: 0.00309

TwinsUK AF: 0.00 AC: 0

ALSPAC AF: 0.000259 AC: 1

ESP6500AA AF: 0.000249 AC: 1

ESP6500EA AF: 0.000120 AC: 1

ExAC AF: 0.00466 AC: 564

Asia WGS AF: 0.0180 AC: 61 AN: 3478

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

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

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.16
BayesDel_addAF	Benign	-0.31	T
BayesDel_noAF	Benign	-0.18
CADD	Benign	20
DANN	Benign	0.75
DEOGEN2	Benign	0.0065	T
Eigen	Uncertain	0.28
Eigen_PC	Uncertain	0.38
FATHMM_MKL	Uncertain	0.82	D
LIST_S2	Benign	0.83	T
MetaRNN	Benign	0.0057	T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	-1.8	N
PhyloP100		5.0
PrimateAI	Uncertain	0.61	T
PROVEAN	Benign	0.15	N
REVEL	Benign	0.21
Sift	Benign	1.0	T
Sift4G	Benign	1.0	T
Polyphen		0.0080	B
Vest4		0.16
MVP		0.60
MPC		0.079
ClinPred		0.017	T
GERP RS		5.6
Varity_R		0.099
gMVP		0.096
Mutation Taster		=66/34	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.0039
dbscSNV1_RF	Benign	0.038
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: rs3732309; hg19: chr2-152372974;