3-124241883-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.263+6940A>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.302 in 152,088 control chromosomes in the GnomAD database, including 8,993 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 0.30 (8993 hom., cov: 32)
• Consequence: KALRN NM_001388419.1 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.0170

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=-0.95).
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.572 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
KALRN	NM_001388419.1	c.263+6940A>G		intron_variant		ENST00000682506.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
KALRN	ENST00000682506.1	c.263+6940A>G		intron_variant			NM_001388419.1	A2

Frequencies

GnomAD3 genomes AF: 0.302 AC: 45850 AN: 151970 Hom.: 8962 Cov.: 32

Gnomad AFR AF: 0.521

Gnomad AMI AF: 0.169

Gnomad AMR AF: 0.284

Gnomad ASJ AF: 0.198

Gnomad EAS AF: 0.589

Gnomad SAS AF: 0.355

Gnomad FIN AF: 0.259

Gnomad MID AF: 0.212

Gnomad NFE AF: 0.161

Gnomad OTH AF: 0.294

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

GnomAD4 genome AF: 0.302 AC: 45926 AN: 152088 Hom.: 8993 Cov.: 32 AF XY: 0.310 AC XY: 23010 AN XY: 74332

Gnomad4 AFR AF: 0.522

Gnomad4 AMR AF: 0.283

Gnomad4 ASJ AF: 0.198

Gnomad4 EAS AF: 0.590

Gnomad4 SAS AF: 0.352

Gnomad4 FIN AF: 0.259

Gnomad4 NFE AF: 0.161

Gnomad4 OTH AF: 0.301

Alfa AF: 0.194 Hom.: 3356

Bravo AF: 0.313

Asia WGS AF: 0.496 AC: 1720 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	3.6
Dann	Benign	0.50

Splicing

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

Publications

LitVar

Other links and lift over

dbSNP: rs4678097; hg19: chr3-123960730; COSMIC: COSV53757324;