rs2286735

Variant names:

• chr10-113629607-G-A
• rs2286735
• NM_198060.4:c.2021C>T

Variant summary

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

The NM_198060.4(NRAP):​c.2021C>T​(p.Ala674Val) variant causes a missense change. The variant allele was found at a frequency of 0.308 in 1,607,510 control chromosomes in the GnomAD database, including 78,212 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.28 (6360 hom., cov: 32)
  • Exomes 𝑓: 0.31 (71852 hom.)
• Consequence: NRAP NM_198060.4 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: 6.92
• Publications: 21 publications found

Genes affected

NRAP (HGNC:7988): (nebulin related anchoring protein) Predicted to enable actin filament binding activity and muscle alpha-actinin binding activity. Predicted to be involved in cardiac muscle thin filament assembly. Predicted to be located in fascia adherens; muscle tendon junction; and myofibril. Predicted to be active in Z disc. [provided by Alliance of Genome Resources, Apr 2022]

NRAP Gene-Disease associations (from GenCC):

• dilated cardiomyopathy

  Inheritance: AR Classification: STRONG Submitted by: ClinGen

ACMG classification

Our verdict: Benign. The variant received -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0049262047).
• BP6: Variant 10-113629607-G-A is Benign according to our data. Variant chr10-113629607-G-A is described in ClinVar as Benign. ClinVar VariationId is 1269749.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AMR) allele frequency at 95% confidence interval = 0.35 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_198060.4. 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
	NRAP	NM_198060.4	MANE Select	c.2021C>T	p.Ala674Val	missense	Exon 19 of 42	NP_932326.2
	NRAP	NM_001261463.2		c.2021C>T	p.Ala674Val	missense	Exon 19 of 42	NP_001248392.1	A0A0A0MRM2
	NRAP	NM_006175.5		c.1916C>T	p.Ala639Val	missense	Exon 18 of 41	NP_006166.3

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	NRAP	ENST00000359988.4	TSL:1 MANE Select	c.2021C>T	p.Ala674Val	missense	Exon 19 of 42	ENSP00000353078.3	Q86VF7-1
	NRAP	ENST00000369358.8	TSL:1	c.2021C>T	p.Ala674Val	missense	Exon 19 of 42	ENSP00000358365.4	A0A0A0MRM2
	NRAP	ENST00000360478.7	TSL:1	c.1916C>T	p.Ala639Val	missense	Exon 18 of 41	ENSP00000353666.3	Q86VF7-4

Frequencies

GnomAD3 genomes AF: 0.285 AC: 43185 AN: 151752 Hom.: 6338 Cov.: 32

Gnomad AFR AF: 0.215

Gnomad AMI AF: 0.219

Gnomad AMR AF: 0.358

Gnomad ASJ AF: 0.291

Gnomad EAS AF: 0.286

Gnomad SAS AF: 0.297

Gnomad FIN AF: 0.309

Gnomad MID AF: 0.232

Gnomad NFE AF: 0.307

Gnomad OTH AF: 0.267

GnomAD2 exomes AF: 0.317 AC: 79598 AN: 251088 AF XY: 0.316

Gnomad AFR exome AF: 0.215

Gnomad AMR exome AF: 0.451

Gnomad ASJ exome AF: 0.275

Gnomad EAS exome AF: 0.280

Gnomad FIN exome AF: 0.300

Gnomad NFE exome AF: 0.310

Gnomad OTH exome AF: 0.296

GnomAD4 exome AF: 0.311 AC: 452188 AN: 1455638 Hom.: 71852 Cov.: 32 AF XY: 0.310 AC XY: 224783 AN XY: 724486

African (AFR) AF: 0.210 AC: 7002 AN: 33386

American (AMR) AF: 0.437 AC: 19557 AN: 44714

Ashkenazi Jewish (ASJ) AF: 0.279 AC: 7294 AN: 26114

East Asian (EAS) AF: 0.253 AC: 10039 AN: 39666

South Asian (SAS) AF: 0.304 AC: 26179 AN: 86126

European-Finnish (FIN) AF: 0.303 AC: 16195 AN: 53370

Middle Eastern (MID) AF: 0.254 AC: 1441 AN: 5670

European-Non Finnish (NFE) AF: 0.313 AC: 346446 AN: 1106402

Other (OTH) AF: 0.300 AC: 18035 AN: 60190

GnomAD4 genome AF: 0.285 AC: 43251 AN: 151872 Hom.: 6360 Cov.: 32 AF XY: 0.288 AC XY: 21379 AN XY: 74200

African (AFR) AF: 0.216 AC: 8953 AN: 41484

American (AMR) AF: 0.358 AC: 5475 AN: 15276

Ashkenazi Jewish (ASJ) AF: 0.291 AC: 1009 AN: 3466

East Asian (EAS) AF: 0.286 AC: 1469 AN: 5140

South Asian (SAS) AF: 0.298 AC: 1434 AN: 4808

European-Finnish (FIN) AF: 0.309 AC: 3257 AN: 10530

Middle Eastern (MID) AF: 0.243 AC: 71 AN: 292

European-Non Finnish (NFE) AF: 0.307 AC: 20828 AN: 67860

Other (OTH) AF: 0.264 AC: 557 AN: 2110

Alfa AF: 0.305 Hom.: 24497

Bravo AF: 0.290

TwinsUK AF: 0.324 AC: 1201

ALSPAC AF: 0.323 AC: 1243

ESP6500AA AF: 0.213 AC: 940

ESP6500EA AF: 0.305 AC: 2620

ExAC AF: 0.310 AC: 37694

Asia WGS AF: 0.277 AC: 966 AN: 3478

EpiCase AF: 0.315

EpiControl AF: 0.314

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	2	not provided (2)
-	-	1	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.16
BayesDel_addAF	Benign	-0.52	T
BayesDel_noAF	Benign	-0.38
CADD	Benign	22
DANN	Uncertain	0.99
DEOGEN2	Benign	0.047	T
Eigen	Benign	-0.049
Eigen_PC	Benign	0.089
FATHMM_MKL	Uncertain	0.96	D
LIST_S2	Uncertain	0.87	D
MetaRNN	Benign	0.0049	T
MetaSVM	Benign	-0.99	T
MutationAssessor	Benign	1.7	L
PhyloP100		6.9
PrimateAI	Uncertain	0.53	T
PROVEAN	Uncertain	-2.5	N
REVEL	Benign	0.092
Sift	Benign	0.078	T
Sift4G	Benign	0.24	T
Polyphen		0.0020	B
Vest4		0.20
MPC		0.077
ClinPred		0.062	T
GERP RS		3.3
Varity_R		0.16
gMVP		0.42
Mutation Taster		=99/1	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: rs2286735; hg19: chr10-115389366; COSMIC: COSV63488541;