rs2289420

Positions:

• chr3-124667095-T-C

Variant summary

Our verdict is Benign. Variant got -13 ACMG points: 0P and 13B. BP4_Strong BP7 BA1

The NM_001388419.1(KALRN):​c.6615T>C​(p.Val2205=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0274 in 1,613,910 control chromosomes in the GnomAD database, including 834 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 0.028 (81 hom., cov: 32)
  • Exomes 𝑓: 0.027 (753 hom.)
• Consequence: KALRN NM_001388419.1 synonymous
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.0870

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

Verdict is Benign. Variant got -13 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.54).
• BP7: Synonymous conserved (PhyloP=-0.087 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.0725 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
KALRN	NM_001388419.1	c.6615T>C	p.Val2205=	synonymous_variant	47/60	ENST00000682506.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
KALRN	ENST00000682506.1	c.6615T>C	p.Val2205=	synonymous_variant	47/60		NM_001388419.1	A2

Frequencies

GnomAD3 genomes AF: 0.0277 AC: 4222 AN: 152208 Hom.: 79 Cov.: 32

Gnomad AFR AF: 0.0274

Gnomad AMI AF: 0.0164

Gnomad AMR AF: 0.0401

Gnomad ASJ AF: 0.0216

Gnomad EAS AF: 0.0784

Gnomad SAS AF: 0.0456

Gnomad FIN AF: 0.00847

Gnomad MID AF: 0.0253

Gnomad NFE AF: 0.0237

Gnomad OTH AF: 0.0220

GnomAD3 exomes AF: 0.0318 AC: 7986 AN: 251264 Hom.: 199 AF XY: 0.0313 AC XY: 4250 AN XY: 135794

Gnomad AFR exome AF: 0.0257

Gnomad AMR exome AF: 0.0482

Gnomad ASJ exome AF: 0.0185

Gnomad EAS exome AF: 0.0891

Gnomad SAS exome AF: 0.0429

Gnomad FIN exome AF: 0.00776

Gnomad NFE exome AF: 0.0214

Gnomad OTH exome AF: 0.0279

GnomAD4 exome AF: 0.0273 AC: 39941 AN: 1461584 Hom.: 753 Cov.: 31 AF XY: 0.0274 AC XY: 19912 AN XY: 727086

Gnomad4 AFR exome AF: 0.0261

Gnomad4 AMR exome AF: 0.0496

Gnomad4 ASJ exome AF: 0.0168

Gnomad4 EAS exome AF: 0.0956

Gnomad4 SAS exome AF: 0.0438

Gnomad4 FIN exome AF: 0.00837

Gnomad4 NFE exome AF: 0.0238

Gnomad4 OTH exome AF: 0.0310

GnomAD4 genome AF: 0.0278 AC: 4241 AN: 152326 Hom.: 81 Cov.: 32 AF XY: 0.0280 AC XY: 2089 AN XY: 74490

Gnomad4 AFR AF: 0.0274

Gnomad4 AMR AF: 0.0406

Gnomad4 ASJ AF: 0.0216

Gnomad4 EAS AF: 0.0788

Gnomad4 SAS AF: 0.0460

Gnomad4 FIN AF: 0.00847

Gnomad4 NFE AF: 0.0237

Gnomad4 OTH AF: 0.0241

Alfa AF: 0.0240 Hom.: 63

Bravo AF: 0.0299

Asia WGS AF: 0.0560 AC: 194 AN: 3478

EpiCase AF: 0.0236

EpiControl AF: 0.0202

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.54
CADD	Benign	5.8
DANN	Benign	0.74

Splicing

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

Publications

LitVar

Other links and lift over

dbSNP: rs2289420; hg19: chr3-124385942; COSMIC: COSV52260007;