3-124260474-A-G

Position:

• chr3-124260474-A-G

Variant summary

Our verdict is Benign. Variant got -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_001388419.1(KALRN):​c.264-4024A>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.439 in 151,942 control chromosomes in the GnomAD database, including 14,770 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 0.44 (14770 hom., cov: 31)
• Consequence: KALRN NM_001388419.1 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.984

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 -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.88).
• BA1: GnomAd4 highest subpopulation (AMR) allele frequency at 95% confidence interval = 0.455 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
KALRN	NM_001388419.1	c.264-4024A>G		intron_variant		ENST00000682506.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
KALRN	ENST00000682506.1	c.264-4024A>G		intron_variant			NM_001388419.1	A2

Frequencies

GnomAD3 genomes AF: 0.438 AC: 66557 AN: 151824 Hom.: 14740 Cov.: 31

Gnomad AFR AF: 0.439

Gnomad AMI AF: 0.359

Gnomad AMR AF: 0.464

Gnomad ASJ AF: 0.413

Gnomad EAS AF: 0.270

Gnomad SAS AF: 0.350

Gnomad FIN AF: 0.453

Gnomad MID AF: 0.402

Gnomad NFE AF: 0.451

Gnomad OTH AF: 0.446

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

GnomAD4 genome AF: 0.439 AC: 66648 AN: 151942 Hom.: 14770 Cov.: 31 AF XY: 0.436 AC XY: 32408 AN XY: 74274

Gnomad4 AFR AF: 0.440

Gnomad4 AMR AF: 0.464

Gnomad4 ASJ AF: 0.413

Gnomad4 EAS AF: 0.271

Gnomad4 SAS AF: 0.349

Gnomad4 FIN AF: 0.453

Gnomad4 NFE AF: 0.451

Gnomad4 OTH AF: 0.441

Alfa AF: 0.454 Hom.: 2475

Bravo AF: 0.443

Asia WGS AF: 0.302 AC: 1049 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.88
CADD	Benign	8.7
DANN	Benign	0.71

Splicing

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

Publications

LitVar

Other links and lift over

dbSNP: rs11929003; hg19: chr3-123979321;