Genetic Variant KALRN:p.His302His (chr3-124269192-T-C) – ACMG Classification: Benign (-10 pts)

Variant summary

Our verdict is Benign. The variant received -10 ACMG points: 0P and 10B. BP6BP7BA1

The NM_001388419.1(KALRN):c.906T>C(p.His302His) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.617 in 1,610,832 control chromosomes in the GnomAD database, including 307,770 homozygotes. Variant has been reported in ClinVar as Benign (no stars).

Frequency

Genomes: 𝑓 0.62 ( 29775 hom., cov: 33)

Exomes 𝑓: 0.62 ( 277995 hom. )

Consequence

KALRN
NM_001388419.1 synonymous

Scores

Clinical Significance

Benign no assertion criteria provided B:1

Conservation

PhyloP100: -1.68

Publications

14 publications found

Variant links:

Genes affected

KALRN (HGNC:4814): (kalirin RhoGEF kinase) Huntington's disease (HD), a neurodegenerative disorder characterized by loss of striatal neurons, is caused by an expansion of a polyglutamine tract in the HD protein huntingtin. This gene encodes a protein that interacts with the huntingtin-associated protein 1, which is a huntingtin binding protein that may function in vesicle trafficking. [provided by RefSeq, Apr 2016]

KALRN links:

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ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -10 ACMG points.

BP6

Variant 3-124269192-T-C is Benign according to our data. Variant chr3-124269192-T-C is described in ClinVar as [Benign]. Clinvar id is 3060559.Status of the report is no_assertion_criteria_provided, 0 stars.

BP7

Synonymous conserved (PhyloP=-1.68 with no splicing effect.

BA1

GnomAd4 highest subpopulation (AMR) allele frequency at 95% confidence interval = 0.649 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
KALRN	NM_001388419.1 link	c.906T>C	p.His302His	synonymous_variant	Exon 5 of 60	ENST00000682506.1	NP_001375348.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
KALRN	ENST00000682506.1 link	c.906T>C	p.His302His	synonymous_variant	Exon 5 of 60		NM_001388419.1	ENSP00000508359.1		A0A804HLI0

Frequencies

GnomAD3 genomes

AF:

0.624

AC:

94847

AN:

151984

Hom.:

29745

Cov.:

show subpopulations

Gnomad AFR

AF:

0.649

Gnomad AMI

AF:

0.548

Gnomad AMR

AF:

0.659

Gnomad ASJ

AF:

0.569

Gnomad EAS

AF:

0.537

Gnomad SAS

AF:

0.628

Gnomad FIN

AF:

0.602

Gnomad MID

AF:

0.601

Gnomad NFE

AF:

0.614

Gnomad OTH

AF:

0.658

GnomAD2 exomes

AF:

0.620

AC:

154702

AN:

249586

AF XY:

0.617

show subpopulations

Gnomad AFR exome

AF:

0.648

Gnomad AMR exome

AF:

0.686

Gnomad ASJ exome

AF:

0.576

Gnomad EAS exome

AF:

0.538

Gnomad FIN exome

AF:

0.610

Gnomad NFE exome

AF:

0.612

Gnomad OTH exome

AF:

0.620

GnomAD4 exome

AF:

0.617

AC:

899517

AN:

1458730

Hom.:

277995

Cov.:

AF XY:

0.616

AC XY:

446472

AN XY:

725092

show subpopulations

African (AFR)

AF:

0.655

AC:

21880

AN:

33420

American (AMR)

AF:

0.684

AC:

30566

AN:

44668

Ashkenazi Jewish (ASJ)

AF:

0.579

AC:

15127

AN:

26118

East Asian (EAS)

AF:

0.508

AC:

20138

AN:

39614

South Asian (SAS)

AF:

0.624

AC:

53801

AN:

86214

European-Finnish (FIN)

AF:

0.600

AC:

31729

AN:

52890

Middle Eastern (MID)

AF:

0.587

AC:

3277

AN:

5586

European-Non Finnish (NFE)

AF:

0.618

AC:

685445

AN:

1109998

Other (OTH)

AF:

0.624

AC:

37554

AN:

60222

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.479

Heterozygous variant carriers

19820

39640

59460

79280

99100

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

AF:

0.624

AC:

94934

AN:

152102

Hom.:

29775

Cov.:

AF XY:

0.623

AC XY:

46317

AN XY:

74360

show subpopulations

African (AFR)

AF:

0.649

AC:

26953

AN:

41506

American (AMR)

AF:

0.660

AC:

10083

AN:

15288

Ashkenazi Jewish (ASJ)

AF:

0.569

AC:

1975

AN:

3470

East Asian (EAS)

AF:

0.537

AC:

2770

AN:

5156

South Asian (SAS)

AF:

0.627

AC:

3022

AN:

4820

European-Finnish (FIN)

AF:

0.602

AC:

6365

AN:

10574

Middle Eastern (MID)

AF:

0.616

AC:

181

AN:

294

European-Non Finnish (NFE)

AF:

0.614

AC:

41705

AN:

67976

Other (OTH)

AF:

0.655

AC:

1382

AN:

2110

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.501

Heterozygous variant carriers

1857

3714

5570

7427

9284

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Alfa

AF:

0.615

Hom.:

71694

Bravo

AF:

0.632

Asia WGS

AF:

0.631

AC:

2195

AN:

3478

EpiCase

AF:

0.617

EpiControl

AF:

0.619

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: no assertion criteria provided

LINK: link

Submissions by phenotype

KALRN-related disorder

Benign:1

Sep 24, 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

BayesDel_noAF

Benign

-0.63

CADD

Benign

0.19

(source)

DANN

Benign

0.51

PhyloP100

-1.7

Mutation Taster

=100/0

polymorphism (auto)

(source)

Splicing

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

Publications

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3-124269192-T-C

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