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GeneBe

3-124269192-T-C

Variant summary

Our verdict is Benign. Variant got -15 ACMG points: 0P and 15B. BP4_StrongBP6_ModerateBP7BA1

The NM_001388419.1(KALRN):c.906T>C(p.His302=) 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. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

Frequency

Genomes: 𝑓 0.62 ( 29775 hom., cov: 33)
Exomes 𝑓: 0.62 ( 277995 hom. )

Consequence

KALRN
NM_001388419.1 synonymous

Scores

2

Clinical Significance

Benign criteria provided, single submitter B:1

Conservation

PhyloP100: -1.68
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]

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ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -15 ACMG points.

BP4
?
    BP4 - Multiple lines of computational evidence suggest no impact on gene or gene product (conservation, evolutionary, splicing impact, etc.)
Computational evidence support a benign effect (BayesDel_noAF=-0.63).
BP6
?
    BP6 - Reputable source recently reports variant as benign, but the evidence is not available to the laboratory to perform an independent evaluation
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 criteria_provided_single_submitter, 1 stars.
BP7
?
    BP7 - A synonymous (silent) variant for which splicing prediction algorithms predict no impact to the splice consensus sequence nor the creation of a new splice site AND the nucleotide is not highly conserved
Synonymous conserved (PhyloP=-1.68 with no splicing effect.
BA1
?
    BA1 - Allele frequency is >5% in Exome Sequencing Project, 1000 Genomes Project, or Exome Aggregation Consortium
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/exons MANE UniProt
KALRNNM_001388419.1 linkuse as main transcriptc.906T>C p.His302= synonymous_variant 5/60 ENST00000682506.1

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Appris UniProt
KALRNENST00000682506.1 linkuse as main transcriptc.906T>C p.His302= synonymous_variant 5/60 NM_001388419.1 A2

Frequencies

GnomAD3 genomes
?
    Genome Aggregation Database, over 76,156 genomes
AF:
0.624
AC:
94847
AN:
151984
Hom.:
29745
Cov.:
33
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
GnomAD3 exomes
AF:
0.620
AC:
154702
AN:
249586
Hom.:
48207
AF XY:
0.617
AC XY:
83544
AN XY:
135384
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 SAS exome
AF:
0.630
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.:
56
AF XY:
0.616
AC XY:
446472
AN XY:
725092
show subpopulations
Gnomad4 AFR exome
AF:
0.655
Gnomad4 AMR exome
AF:
0.684
Gnomad4 ASJ exome
AF:
0.579
Gnomad4 EAS exome
AF:
0.508
Gnomad4 SAS exome
AF:
0.624
Gnomad4 FIN exome
AF:
0.600
Gnomad4 NFE exome
AF:
0.618
Gnomad4 OTH exome
AF:
0.624
GnomAD4 genome
?
    Genome Aggregation Database, over 76,156 genomes
AF:
0.624
AC:
94934
AN:
152102
Hom.:
29775
Cov.:
33
AF XY:
0.623
AC XY:
46317
AN XY:
74360
show subpopulations
Gnomad4 AFR
AF:
0.649
Gnomad4 AMR
AF:
0.660
Gnomad4 ASJ
AF:
0.569
Gnomad4 EAS
AF:
0.537
Gnomad4 SAS
AF:
0.627
Gnomad4 FIN
AF:
0.602
Gnomad4 NFE
AF:
0.614
Gnomad4 OTH
AF:
0.655
Alfa
AF:
0.616
Hom.:
55337
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: criteria provided, single submitter
LINK: link

Submissions by phenotype

KALRN-related disorder Benign:1
Benign, criteria provided, single submitterclinical testingPreventionGenetics, part of Exact SciencesSep 24, 2019This 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
Dann
Benign
0.51

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.

Other links and lift over

dbSNP: rs2272486; hg19: chr3-123988039; COSMIC: COSV53774804; COSMIC: COSV53774804; API