rs573186

Variant names:

• chr3-124459429-T-C
• rs573186
• NM_001388419.1:c.3855-2461T>C

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_001388419.1(KALRN):​c.3855-2461T>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.546 in 152,078 control chromosomes in the GnomAD database, including 23,693 homozygotes. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency: Genomes: 𝑓 0.55 (23693 hom., cov: 32)
• Consequence: KALRN NM_001388419.1 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.0930
• Publications: 4 publications found

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]

ACMG classification

Our verdict: Benign. The variant received -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.95).
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.619 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
KALRN	NM_001388419.1	c.3855-2461T>C		intron_variant	Intron 23 of 59	ENST00000682506.1	NP_001375348.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
KALRN	ENST00000682506.1	c.3855-2461T>C		intron_variant	Intron 23 of 59		NM_001388419.1	ENSP00000508359.1

Frequencies

GnomAD3 genomes AF: 0.546 AC: 82915 AN: 151960 Hom.: 23683 Cov.: 32

Gnomad AFR AF: 0.504

Gnomad AMI AF: 0.693

Gnomad AMR AF: 0.446

Gnomad ASJ AF: 0.600

Gnomad EAS AF: 0.114

Gnomad SAS AF: 0.580

Gnomad FIN AF: 0.507

Gnomad MID AF: 0.652

Gnomad NFE AF: 0.624

Gnomad OTH AF: 0.563

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome AF: 0.546 AC: 82959 AN: 152078 Hom.: 23693 Cov.: 32 AF XY: 0.537 AC XY: 39909 AN XY: 74358

African (AFR) AF: 0.504 AC: 20888 AN: 41472

American (AMR) AF: 0.445 AC: 6802 AN: 15284

Ashkenazi Jewish (ASJ) AF: 0.600 AC: 2080 AN: 3468

East Asian (EAS) AF: 0.114 AC: 592 AN: 5178

South Asian (SAS) AF: 0.580 AC: 2793 AN: 4812

European-Finnish (FIN) AF: 0.507 AC: 5368 AN: 10594

Middle Eastern (MID) AF: 0.636 AC: 187 AN: 294

European-Non Finnish (NFE) AF: 0.624 AC: 42438 AN: 67958

Other (OTH) AF: 0.560 AC: 1180 AN: 2108

Alfa AF: 0.595 Hom.: 53056

Bravo AF: 0.536

Asia WGS AF: 0.375 AC: 1306 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.95
CADD	Benign	2.0
DANN	Benign	0.35
PhyloP100		-0.093
Mutation Taster		=100/0	polymorphism (auto)

Splicing

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

Other links and lift over

dbSNP: rs573186; hg19: chr3-124178276; COSMIC: COSV53757908;