Genetic Variant NHLRC2:p.Val314Ile (chr10-113884281-G-A) – ACMG Classification: Benign (-13 pts)

Variant summary

Our verdict is Benign. The variant received -13 ACMG points: 0P and 13B. BP4_StrongBP6BA1

The NM_198514.4(NHLRC2):c.940G>A(p.Val314Ile) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.276 in 1,608,448 control chromosomes in the GnomAD database, including 63,487 homozygotes. In-silico tool predicts a benign outcome for this variant. 13/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (no stars).

Frequency

Genomes: 𝑓 0.25 ( 5162 hom., cov: 32)

Exomes 𝑓: 0.28 ( 58325 hom. )

Consequence

NHLRC2
NM_198514.4 missense

Scores

Clinical Significance

Benign no assertion criteria provided B:1

Conservation

PhyloP100: 2.65

Publications

33 publications found

Variant links:

Genes affected

NHLRC2 (HGNC:24731): (NHL repeat containing 2) Located in cytosol. [provided by Alliance of Genome Resources, Apr 2022]

NHLRC2 Gene-Disease associations (from GenCC):

fibrosis, neurodegeneration, and cerebral angiomatosis
Inheritance: AR Classification: DEFINITIVE, STRONG, LIMITED Submitted by: G2P, Labcorp Genetics (formerly Invitae), Ambry Genetics

NHLRC2 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -13 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.0014792085).

BP6

Variant 10-113884281-G-A is Benign according to our data. Variant chr10-113884281-G-A is described in ClinVar as Benign. ClinVar VariationId is 3059194.Status of the report is no_assertion_criteria_provided, 0 stars.

BA1

GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.316 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
NHLRC2	NM_198514.4 link	c.940G>A	p.Val314Ile	missense_variant	Exon 5 of 11	ENST00000369301.3	NP_940916.2	Q8NBF2-1Q7Z658
NHLRC2	XM_011539769.4 link	c.940G>A	p.Val314Ile	missense_variant	Exon 5 of 11		XP_011538071.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
NHLRC2	ENST00000369301.3 link	c.940G>A	p.Val314Ile	missense_variant	Exon 5 of 11	2	NM_198514.4	ENSP00000358307.3		Q8NBF2-1

Frequencies

GnomAD3 genomes

AF:

0.250

AC:

37925

AN:

151572

Hom.:

5157

Cov.:

show subpopulations

Gnomad AFR

AF:

0.152

Gnomad AMI

AF:

0.241

Gnomad AMR

AF:

0.254

Gnomad ASJ

AF:

0.240

Gnomad EAS

AF:

0.328

Gnomad SAS

AF:

0.200

Gnomad FIN

AF:

0.392

Gnomad MID

AF:

0.225

Gnomad NFE

AF:

0.287

Gnomad OTH

AF:

0.226

GnomAD2 exomes

AF:

0.276

AC:

69339

AN:

250812

AF XY:

0.273

show subpopulations

Gnomad AFR exome

AF:

0.149

Gnomad AMR exome

AF:

0.271

Gnomad ASJ exome

AF:

0.217

Gnomad EAS exome

AF:

0.330

Gnomad FIN exome

AF:

0.394

Gnomad NFE exome

AF:

0.291

Gnomad OTH exome

AF:

0.270

GnomAD4 exome

AF:

0.279

AC:

406600

AN:

1456756

Hom.:

58325

Cov.:

AF XY:

0.277

AC XY:

201023

AN XY:

724860

show subpopulations

African (AFR)

AF:

0.139

AC:

4647

AN:

33356

American (AMR)

AF:

0.266

AC:

11894

AN:

44658

Ashkenazi Jewish (ASJ)

AF:

0.223

AC:

5803

AN:

25996

East Asian (EAS)

AF:

0.285

AC:

11252

AN:

39522

South Asian (SAS)

AF:

0.203

AC:

17453

AN:

86078

European-Finnish (FIN)

AF:

0.386

AC:

20584

AN:

53268

Middle Eastern (MID)

AF:

0.189

AC:

1083

AN:

5740

European-Non Finnish (NFE)

AF:

0.287

AC:

317986

AN:

1108008

Other (OTH)

AF:

0.264

AC:

15898

AN:

60130

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.481

Heterozygous variant carriers

13511

27022

40532

54043

67554

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

10462

20924

31386

41848

52310

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.250

AC:

37937

AN:

151692

Hom.:

5162

Cov.:

AF XY:

0.253

AC XY:

18745

AN XY:

74144

show subpopulations

African (AFR)

AF:

0.152

AC:

6289

AN:

41500

American (AMR)

AF:

0.254

AC:

3863

AN:

15222

Ashkenazi Jewish (ASJ)

AF:

0.240

AC:

832

AN:

3462

East Asian (EAS)

AF:

0.329

AC:

1697

AN:

5160

South Asian (SAS)

AF:

0.200

AC:

964

AN:

4824

European-Finnish (FIN)

AF:

0.392

AC:

4134

AN:

10536

Middle Eastern (MID)

AF:

0.221

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.287

AC:

19403

AN:

67676

Other (OTH)

AF:

0.223

AC:

471

AN:

2108

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.501

Heterozygous variant carriers

1426

2852

4277

5703

7129

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

398

796

1194

1592

1990

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.272

Hom.:

26727

Bravo

AF:

0.238

TwinsUK

AF:

0.295

AC:

1095

ALSPAC

AF:

0.294

AC:

1134

ESP6500AA

AF:

0.155

AC:

684

ESP6500EA

AF:

0.282

AC:

2422

ExAC

AF:

0.272

AC:

32986

Asia WGS

AF:

0.252

AC:

875

AN:

3478

EpiCase

AF:

0.271

EpiControl

AF:

0.265

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: no assertion criteria provided

LINK: link

Submissions by phenotype

NHLRC2-related disorder

Benign:1

Oct 21, 2019

PreventionGenetics, part of Exact Sciences

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

This variant is classified as benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.066

BayesDel_addAF

Benign

-0.52

BayesDel_noAF

Benign

-0.37

CADD

Benign

(source)

DANN

Uncertain

0.99

DEOGEN2

Benign

0.0015

Eigen

Benign

-0.074

Eigen_PC

Benign

0.073

FATHMM_MKL

Uncertain

0.85

LIST_S2

Benign

0.83

MetaRNN

Benign

0.0015

MetaSVM

Benign

-0.99

MutationAssessor

Benign

1.0

PhyloP100

2.6

PrimateAI

Benign

0.36

PROVEAN

Benign

0.25

REVEL

Uncertain

0.30

Sift

Benign

0.43

Sift4G

Benign

0.64

Polyphen

0.55

Vest4

0.047

MPC

0.11

ClinPred

0.014

GERP RS

5.0

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Varity_R

0.082

gMVP

0.24

Mutation Taster

=90/10

polymorphism (auto)

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.020

Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over