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GeneBe

rs2289843

Positions:

Variant summary

Our verdict is Benign. Variant got -13 ACMG points: 0P and 13B. BP4_ModerateBP6_ModerateBP7BA1

The NM_001388419.1(KALRN):​c.4104A>T​(p.Ala1368=) variant causes a splice region, synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.132 in 1,607,274 control chromosomes in the GnomAD database, including 19,812 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

Frequency

Genomes: 𝑓 0.12 ( 1918 hom., cov: 32)
Exomes 𝑓: 0.13 ( 17894 hom. )

Consequence

KALRN
NM_001388419.1 splice_region, synonymous

Scores

2

Clinical Significance

Benign criteria provided, single submitter B:1

Conservation

PhyloP100: 0.948
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 -13 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=-0.42).
BP6
?
    BP6 - Reputable source recently reports variant as benign, but the evidence is not available to the laboratory to perform an independent evaluation
Variant 3-124477247-A-T is Benign according to our data. Variant chr3-124477247-A-T is described in ClinVar as [Benign]. Clinvar id is 3060446.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=0.948 with no splicing effect.
BA1
?
    BA1 - Allele frequency is >5% in Exome Sequencing Project, 1000 Genomes Project, or Exome Aggregation Consortium
GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.486 is higher than 0.05.

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE UniProt
KALRNNM_001388419.1 linkuse as main transcriptc.4104A>T p.Ala1368= splice_region_variant, synonymous_variant 27/60 ENST00000682506.1

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Appris UniProt
KALRNENST00000682506.1 linkuse as main transcriptc.4104A>T p.Ala1368= splice_region_variant, synonymous_variant 27/60 NM_001388419.1 A2

Frequencies

GnomAD3 genomes
?
    Genome Aggregation Database, over 76,156 genomes
AF:
0.123
AC:
18652
AN:
152082
Hom.:
1907
Cov.:
32
show subpopulations
Gnomad AFR
AF:
0.0356
Gnomad AMI
AF:
0.0932
Gnomad AMR
AF:
0.224
Gnomad ASJ
AF:
0.0568
Gnomad EAS
AF:
0.502
Gnomad SAS
AF:
0.174
Gnomad FIN
AF:
0.209
Gnomad MID
AF:
0.0510
Gnomad NFE
AF:
0.111
Gnomad OTH
AF:
0.114
GnomAD3 exomes
AF:
0.172
AC:
43123
AN:
251102
Hom.:
5636
AF XY:
0.165
AC XY:
22392
AN XY:
135704
show subpopulations
Gnomad AFR exome
AF:
0.0345
Gnomad AMR exome
AF:
0.301
Gnomad ASJ exome
AF:
0.0554
Gnomad EAS exome
AF:
0.502
Gnomad SAS exome
AF:
0.153
Gnomad FIN exome
AF:
0.198
Gnomad NFE exome
AF:
0.111
Gnomad OTH exome
AF:
0.143
GnomAD4 exome
AF:
0.133
AC:
193792
AN:
1455078
Hom.:
17894
Cov.:
29
AF XY:
0.132
AC XY:
95876
AN XY:
724346
show subpopulations
Gnomad4 AFR exome
AF:
0.0304
Gnomad4 AMR exome
AF:
0.292
Gnomad4 ASJ exome
AF:
0.0555
Gnomad4 EAS exome
AF:
0.539
Gnomad4 SAS exome
AF:
0.155
Gnomad4 FIN exome
AF:
0.193
Gnomad4 NFE exome
AF:
0.113
Gnomad4 OTH exome
AF:
0.131
GnomAD4 genome
?
    Genome Aggregation Database, over 76,156 genomes
AF:
0.123
AC:
18668
AN:
152196
Hom.:
1918
Cov.:
32
AF XY:
0.132
AC XY:
9853
AN XY:
74408
show subpopulations
Gnomad4 AFR
AF:
0.0355
Gnomad4 AMR
AF:
0.225
Gnomad4 ASJ
AF:
0.0568
Gnomad4 EAS
AF:
0.502
Gnomad4 SAS
AF:
0.173
Gnomad4 FIN
AF:
0.209
Gnomad4 NFE
AF:
0.111
Gnomad4 OTH
AF:
0.118
Alfa
AF:
0.104
Hom.:
300
Bravo
AF:
0.122
Asia WGS
AF:
0.288
AC:
1002
AN:
3478
EpiCase
AF:
0.107
EpiControl
AF:
0.102

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 SciencesOct 21, 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
-0.42
CADD
Benign
14
DANN
Benign
0.83

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: rs2289843; hg19: chr3-124196094; COSMIC: COSV53756919; API