Genetic Variant NM_001388419.1:c.2049G>A (chr3-124395221-G-A) – ACMG Classification: Benign (-12 pts)

Variant summary

Our verdict is Benign. Variant got -12 ACMG points: 0P and 12B. BP4_ModerateBP6BP7BA1

The NM_001388419.1(KALRN):c.2049G>A(p.Lys683Lys) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.148 in 1,612,574 control chromosomes in the GnomAD database, including 19,023 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (no stars).

Frequency

Genomes: 𝑓 0.12 ( 1273 hom., cov: 30)

Exomes 𝑓: 0.15 ( 17750 hom. )

Consequence

KALRN
NM_001388419.1 synonymous

Scores

Clinical Significance

Benign no assertion criteria provided B:1

Conservation

PhyloP100: 0.534

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 made for transcript

Verdict is Benign. Variant got -12 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.45).

BP6

Variant 3-124395221-G-A is Benign according to our data. Variant chr3-124395221-G-A is described in ClinVar as [Benign]. Clinvar id is 3056443.Status of the report is no_assertion_criteria_provided, 0 stars.

BP7

Synonymous conserved (PhyloP=0.534 with no splicing effect.

BA1

GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.162 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
KALRN	NM_001388419.1 link	c.2049G>A	p.Lys683Lys	synonymous_variant	Exon 12 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.2049G>A	p.Lys683Lys	synonymous_variant	Exon 12 of 60		NM_001388419.1	ENSP00000508359.1		A0A804HLI0

Frequencies

GnomAD3 genomes

AF:

0.117

AC:

17657

AN:

150956

Hom.:

1274

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0393

Gnomad AMI

AF:

0.166

Gnomad AMR

AF:

0.133

Gnomad ASJ

AF:

0.129

Gnomad EAS

AF:

0.0215

Gnomad SAS

AF:

0.105

Gnomad FIN

AF:

0.129

Gnomad MID

AF:

0.0886

Gnomad NFE

AF:

0.164

Gnomad OTH

AF:

0.152

GnomAD3 exomes

AF:

0.127

AC:

31693

AN:

250468

Hom.:

2314

AF XY:

0.130

AC XY:

17562

AN XY:

135334

show subpopulations

Gnomad AFR exome

AF:

0.0349

Gnomad AMR exome

AF:

0.109

Gnomad ASJ exome

AF:

0.130

Gnomad EAS exome

AF:

0.0226

Gnomad SAS exome

AF:

0.112

Gnomad FIN exome

AF:

0.131

Gnomad NFE exome

AF:

0.164

Gnomad OTH exome

AF:

0.138

GnomAD4 exome

AF:

0.151

AC:

220341

AN:

1461500

Hom.:

17750

Cov.:

AF XY:

0.150

AC XY:

109186

AN XY:

727052

show subpopulations

Gnomad4 AFR exome

AF:

0.0341

Gnomad4 AMR exome

AF:

0.113

Gnomad4 ASJ exome

AF:

0.133

Gnomad4 EAS exome

AF:

0.0186

Gnomad4 SAS exome

AF:

0.112

Gnomad4 FIN exome

AF:

0.134

Gnomad4 NFE exome

AF:

0.166

Gnomad4 OTH exome

AF:

0.142

GnomAD4 genome

AF:

0.117

AC:

17655

AN:

151074

Hom.:

1273

Cov.:

AF XY:

0.115

AC XY:

8488

AN XY:

73716

show subpopulations

Gnomad4 AFR

AF:

0.0392

Gnomad4 AMR

AF:

0.133

Gnomad4 ASJ

AF:

0.129

Gnomad4 EAS

AF:

0.0217

Gnomad4 SAS

AF:

0.105

Gnomad4 FIN

AF:

0.129

Gnomad4 NFE

AF:

0.164

Gnomad4 OTH

AF:

0.150

Alfa

AF:

0.146

Hom.:

899

Bravo

AF:

0.115

Asia WGS

AF:

0.0810

AC:

281

AN:

3478

EpiCase

AF:

0.162

EpiControl

AF:

0.165

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: no assertion criteria provided

LINK: link

Submissions by phenotype

KALRN-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

BayesDel_noAF

Benign

-0.45

CADD

Benign

6.6

DANN

Benign

0.62

Splicing

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

Publications

LitVar

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over