Genetic Variant KALRN:p.Lys44Lys (chr3-124228048-G-A) – ACMG Classification: Benign (-11 pts)

Variant summary

Our verdict is Benign. The variant received -11 ACMG points: 0P and 11B. BP4BP6BP7BA1

The NM_001388419.1(KALRN):c.132G>A(p.Lys44Lys) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0604 in 1,613,456 control chromosomes in the GnomAD database, including 4,897 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (no stars).

Frequency

Genomes: 𝑓 0.099 ( 1132 hom., cov: 31)

Exomes 𝑓: 0.056 ( 3765 hom. )

Consequence

KALRN
NM_001388419.1 synonymous

Scores

Clinical Significance

Benign no assertion criteria provided B:1

Conservation

PhyloP100: 3.01

Publications

10 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 -11 ACMG points.

BP4

Computational evidence support a benign effect (REVEL=0.207).

BP6

Variant 3-124228048-G-A is Benign according to our data. Variant chr3-124228048-G-A is described in ClinVar as [Benign]. Clinvar id is 3060740.Status of the report is no_assertion_criteria_provided, 0 stars.

BP7

Synonymous conserved (PhyloP=3.01 with no splicing effect.

BA1

GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.194 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
KALRN	NM_001388419.1 link	c.132G>A	p.Lys44Lys	synonymous_variant	Exon 2 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.132G>A	p.Lys44Lys	synonymous_variant	Exon 2 of 60		NM_001388419.1	ENSP00000508359.1		A0A804HLI0

Frequencies

GnomAD3 genomes

AF:

0.0989

AC:

15037

AN:

152036

Hom.:

1129

Cov.:

show subpopulations

Gnomad AFR

AF:

0.198

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.119

Gnomad ASJ

AF:

0.0513

Gnomad EAS

AF:

0.181

Gnomad SAS

AF:

0.109

Gnomad FIN

AF:

0.0564

Gnomad MID

AF:

0.111

Gnomad NFE

AF:

0.0382

Gnomad OTH

AF:

0.0800

GnomAD2 exomes

AF:

0.0896

AC:

22534

AN:

251414

AF XY:

0.0831

show subpopulations

Gnomad AFR exome

AF:

0.204

Gnomad AMR exome

AF:

0.173

Gnomad ASJ exome

AF:

0.0590

Gnomad EAS exome

AF:

0.183

Gnomad FIN exome

AF:

0.0526

Gnomad NFE exome

AF:

0.0389

Gnomad OTH exome

AF:

0.0779

GnomAD4 exome

AF:

0.0563

AC:

82344

AN:

1461302

Hom.:

3765

Cov.:

AF XY:

0.0564

AC XY:

41010

AN XY:

726974

show subpopulations

African (AFR)

AF:

0.216

AC:

7234

AN:

33456

American (AMR)

AF:

0.162

AC:

7265

AN:

44720

Ashkenazi Jewish (ASJ)

AF:

0.0594

AC:

1552

AN:

26128

East Asian (EAS)

AF:

0.186

AC:

7376

AN:

39688

South Asian (SAS)

AF:

0.104

AC:

8934

AN:

86234

European-Finnish (FIN)

AF:

0.0541

AC:

2890

AN:

53418

Middle Eastern (MID)

AF:

0.0758

AC:

437

AN:

5764

European-Non Finnish (NFE)

AF:

0.0380

AC:

42282

AN:

1111520

Other (OTH)

AF:

0.0724

AC:

4374

AN:

60374

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.460

Heterozygous variant carriers

3869

7738

11607

15476

19345

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

AF:

0.0990

AC:

15069

AN:

152154

Hom.:

1132

Cov.:

AF XY:

0.101

AC XY:

7514

AN XY:

74398

show subpopulations

African (AFR)

AF:

0.198

AC:

8205

AN:

41486

American (AMR)

AF:

0.119

AC:

1824

AN:

15280

Ashkenazi Jewish (ASJ)

AF:

0.0513

AC:

178

AN:

3472

East Asian (EAS)

AF:

0.180

AC:

934

AN:

5178

South Asian (SAS)

AF:

0.109

AC:

528

AN:

4822

European-Finnish (FIN)

AF:

0.0564

AC:

597

AN:

10590

Middle Eastern (MID)

AF:

0.122

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.0382

AC:

2598

AN:

68010

Other (OTH)

AF:

0.0801

AC:

169

AN:

2110

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.510

Heterozygous variant carriers

675

1350

2026

2701

3376

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Alfa

AF:

0.0684

Hom.:

448

Bravo

AF:

0.109

Asia WGS

AF:

0.176

AC:

610

AN:

3478

EpiCase

AF:

0.0421

EpiControl

AF:

0.0412

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: no assertion criteria provided

LINK: link

Submissions by phenotype

KALRN-related disorder

Benign:1

Nov 18, 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

-0.47

CADD

Benign

(source)

DANN

Benign

0.62

PhyloP100

3.0

PromoterAI

0.0020

Neutral

(source)

Mutation Taster

=95/5

polymorphism (auto)

(source)

Splicing

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

Publications

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3-124228048-G-A

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