Genetic Variant KALRN:p.Ser447Ser (chr3-124329917-C-T) – 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.1341C>T(p.Ser447Ser) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0859 in 1,613,416 control chromosomes in the GnomAD database, including 6,590 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (no stars).

Frequency

Genomes: 𝑓 0.10 ( 908 hom., cov: 31)

Exomes 𝑓: 0.084 ( 5682 hom. )

Consequence

KALRN
NM_001388419.1 synonymous

Scores

Clinical Significance

Benign no assertion criteria provided B:1

Conservation

PhyloP100: -5.44

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=0.269).

BP6

Variant 3-124329917-C-T is Benign according to our data. Variant chr3-124329917-C-T is described in ClinVar as [Benign]. Clinvar id is 3057229.Status of the report is no_assertion_criteria_provided, 0 stars.

BP7

Synonymous conserved (PhyloP=-5.44 with no splicing effect.

BA1

GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.15 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
KALRN	NM_001388419.1 link	c.1341C>T	p.Ser447Ser	synonymous_variant	Exon 8 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.1341C>T	p.Ser447Ser	synonymous_variant	Exon 8 of 60		NM_001388419.1	ENSP00000508359.1		A0A804HLI0

Frequencies

GnomAD3 genomes

AF:

0.103

AC:

15576

AN:

151734

Hom.:

908

Cov.:

show subpopulations

Gnomad AFR

AF:

0.144

Gnomad AMI

AF:

0.133

Gnomad AMR

AF:

0.104

Gnomad ASJ

AF:

0.139

Gnomad EAS

AF:

0.160

Gnomad SAS

AF:

0.0873

Gnomad FIN

AF:

0.0685

Gnomad MID

AF:

0.153

Gnomad NFE

AF:

0.0762

Gnomad OTH

AF:

0.121

GnomAD2 exomes

AF:

0.0961

AC:

24140

AN:

251236

AF XY:

0.0944

show subpopulations

Gnomad AFR exome

AF:

0.147

Gnomad AMR exome

AF:

0.105

Gnomad ASJ exome

AF:

0.145

Gnomad EAS exome

AF:

0.165

Gnomad FIN exome

AF:

0.0705

Gnomad NFE exome

AF:

0.0760

Gnomad OTH exome

AF:

0.104

GnomAD4 exome

AF:

0.0842

AC:

123068

AN:

1461564

Hom.:

5682

Cov.:

AF XY:

0.0846

AC XY:

61533

AN XY:

727066

show subpopulations

African (AFR)

AF:

0.141

AC:

4718

AN:

33466

American (AMR)

AF:

0.105

AC:

4704

AN:

44710

Ashkenazi Jewish (ASJ)

AF:

0.147

AC:

3835

AN:

26132

East Asian (EAS)

AF:

0.149

AC:

5894

AN:

39672

South Asian (SAS)

AF:

0.0937

AC:

8077

AN:

86224

European-Finnish (FIN)

AF:

0.0725

AC:

3869

AN:

53400

Middle Eastern (MID)

AF:

0.108

AC:

625

AN:

5768

European-Non Finnish (NFE)

AF:

0.0772

AC:

85786

AN:

1111814

Other (OTH)

AF:

0.0921

AC:

5560

AN:

60378

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.470

Heterozygous variant carriers

5413

10827

16240

21654

27067

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

AF:

0.103

AC:

15584

AN:

151852

Hom.:

908

Cov.:

AF XY:

0.102

AC XY:

7537

AN XY:

74200

show subpopulations

African (AFR)

AF:

0.144

AC:

5956

AN:

41346

American (AMR)

AF:

0.104

AC:

1589

AN:

15254

Ashkenazi Jewish (ASJ)

AF:

0.139

AC:

483

AN:

3466

East Asian (EAS)

AF:

0.159

AC:

817

AN:

5132

South Asian (SAS)

AF:

0.0864

AC:

415

AN:

4806

European-Finnish (FIN)

AF:

0.0685

AC:

724

AN:

10566

Middle Eastern (MID)

AF:

0.161

AC:

AN:

292

European-Non Finnish (NFE)

AF:

0.0762

AC:

5179

AN:

67978

Other (OTH)

AF:

0.120

AC:

253

AN:

2100

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.522

Heterozygous variant carriers

704

1407

2111

2814

3518

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Alfa

AF:

0.0900

Hom.:

1070

Bravo

AF:

0.108

Asia WGS

AF:

0.111

AC:

386

AN:

3478

EpiCase

AF:

0.0829

EpiControl

AF:

0.0868

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: no assertion criteria provided

LINK: link

Submissions by phenotype

KALRN-related disorder

Benign:1

Nov 25, 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

-0.70

CADD

Benign

1.0

(source)

DANN

Benign

0.54

PhyloP100

-5.4

Mutation Taster

=84/16

polymorphism (auto)

(source)

Splicing

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

Publications

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3-124329917-C-T

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over