3-124395221-G-A

Variant summary

Our verdict is Benign. Variant got -13 ACMG points: 0P and 13B. BP4_Moderate BP6_Moderate BP7 BA1

The NM_001388419.1(KALRN):c.2049G>A(p.Lys683=) 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 (★).

• Frequency:
  • Genomes: 𝑓 0.12 (1273 hom., cov: 30)
  • Exomes 𝑓: 0.15 (17750 hom.)
• Consequence: KALRN NM_001388419.1 synonymous
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 0.534

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=-0.45).
• 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 criteria_provided_single_submitter, 1 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/exons	MANE	UniProt
KALRN	NM_001388419.1	c.2049G>A	p.Lys683=	synonymous_variant	12/60	ENST00000682506.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
KALRN	ENST00000682506.1	c.2049G>A	p.Lys683=	synonymous_variant	12/60		NM_001388419.1	A2

Frequencies

GnomAD3 genomes AF: 0.117 AC: 17657 AN: 150956 Hom.: 1274 Cov.: 30

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

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.: 32 AF XY: 0.150 AC XY: 109186 AN XY: 727052

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.: 30 AF XY: 0.115 AC XY: 8488 AN XY: 73716

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: criteria provided, single submitter

Submissions by phenotype

KALRN-related disorder Benign:1

Benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Oct 21, 2019

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

Other links and lift over

dbSNP: rs9841322; hg19: chr3-124114068; COSMIC: COSV53757850;