Genetic Variant KALRN:p.Ser375Ser (chr3-124326012-C-T) – ACMG Classification: Benign (-9 pts)

Variant summary

Our verdict is Benign. The variant received -9 ACMG points: 0P and 9B. BP4_ModerateBP6_ModerateBP7BS2

The NM_001388419.1(KALRN):c.1125C>T(p.Ser375Ser) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00798 in 1,612,926 control chromosomes in the GnomAD database, including 66 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★).

Frequency

Genomes: 𝑓 0.0077 ( 11 hom., cov: 32)

Exomes 𝑓: 0.0080 ( 55 hom. )

Consequence

KALRN
NM_001388419.1 synonymous

Scores

Clinical Significance

Likely benign criteria provided, single submitter B:1

Conservation

PhyloP100: -5.16

Publications

3 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 -9 ACMG points.

BP4

Computational evidence support a benign effect (REVEL=0.153).

BP6

Variant 3-124326012-C-T is Benign according to our data. Variant chr3-124326012-C-T is described in ClinVar as [Likely_benign]. Clinvar id is 2654085.Status of the report is criteria_provided_single_submitter, 1 stars.

BP7

Synonymous conserved (PhyloP=-5.16 with no splicing effect.

BS2

High AC in GnomAd4 at 1179 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
KALRN	NM_001388419.1 link	c.1125C>T	p.Ser375Ser	synonymous_variant	Exon 7 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.1125C>T	p.Ser375Ser	synonymous_variant	Exon 7 of 60		NM_001388419.1	ENSP00000508359.1		A0A804HLI0

Frequencies

GnomAD3 genomes

AF:

0.00774

AC:

1177

AN:

152134

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00705

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00687

Gnomad ASJ

AF:

0.0193

Gnomad EAS

AF:

0.00849

Gnomad SAS

AF:

0.00228

Gnomad FIN

AF:

0.00104

Gnomad MID

AF:

0.0222

Gnomad NFE

AF:

0.00910

Gnomad OTH

AF:

0.0100

GnomAD2 exomes

AF:

0.00691

AC:

1721

AN:

249216

AF XY:

0.00686

show subpopulations

Gnomad AFR exome

AF:

0.00625

Gnomad AMR exome

AF:

0.00375

Gnomad ASJ exome

AF:

0.0218

Gnomad EAS exome

AF:

0.00943

Gnomad FIN exome

AF:

0.00167

Gnomad NFE exome

AF:

0.00843

Gnomad OTH exome

AF:

0.00945

GnomAD4 exome

AF:

0.00801

AC:

11694

AN:

1460674

Hom.:

Cov.:

AF XY:

0.00785

AC XY:

5706

AN XY:

726574

show subpopulations

African (AFR)

AF:

0.00720

AC:

241

AN:

33472

American (AMR)

AF:

0.00412

AC:

184

AN:

44622

Ashkenazi Jewish (ASJ)

AF:

0.0211

AC:

550

AN:

26124

East Asian (EAS)

AF:

0.0109

AC:

433

AN:

39696

South Asian (SAS)

AF:

0.00194

AC:

167

AN:

85922

European-Finnish (FIN)

AF:

0.00221

AC:

118

AN:

53278

Middle Eastern (MID)

AF:

0.0118

AC:

AN:

5768

European-Non Finnish (NFE)

AF:

0.00845

AC:

9387

AN:

1111450

Other (OTH)

AF:

0.00905

AC:

546

AN:

60342

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.491

Heterozygous variant carriers

593

1186

1778

2371

2964

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

AF:

0.00774

AC:

1179

AN:

152252

Hom.:

Cov.:

AF XY:

0.00689

AC XY:

513

AN XY:

74438

show subpopulations

African (AFR)

AF:

0.00703

AC:

292

AN:

41550

American (AMR)

AF:

0.00686

AC:

105

AN:

15300

Ashkenazi Jewish (ASJ)

AF:

0.0193

AC:

AN:

3472

East Asian (EAS)

AF:

0.00851

AC:

AN:

5170

South Asian (SAS)

AF:

0.00228

AC:

AN:

4818

European-Finnish (FIN)

AF:

0.00104

AC:

AN:

10608

Middle Eastern (MID)

AF:

0.0238

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.00910

AC:

619

AN:

68014

Other (OTH)

AF:

0.0109

AC:

AN:

2114

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.498

Heterozygous variant carriers

127

191

254

318

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Alfa

AF:

0.00689

Hom.:

Bravo

AF:

0.00788

Asia WGS

AF:

0.0150

AC:

AN:

3478

EpiCase

AF:

0.00862

EpiControl

AF:

0.00975

ClinVar

Significance: Likely benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not provided

Benign:1

Dec 01, 2022

CeGaT Center for Human Genetics Tuebingen

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

KALRN: BP4, BP7, BS2 -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.72

CADD

Benign

0.60

(source)

DANN

Benign

0.74

PhyloP100

-5.2

Mutation Taster

=84/16

polymorphism

(source)

Splicing

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

Publications

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3-124326012-C-T

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