chr3-124562757-G-A

Position:

• chr3-124562757-G-A

Variant summary

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

The NM_001388419.1(KALRN):​c.4936-86G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.116 in 1,175,368 control chromosomes in the GnomAD database, including 12,279 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 0.14 (2493 hom., cov: 32)
  • Exomes 𝑓: 0.11 (9786 hom.)
• Consequence: KALRN NM_001388419.1 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.551

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]

LOC105374076 (HGNC:):

ACMG classification

Verdict is Benign. Variant got -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.92).
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.605 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
KALRN	NM_001388419.1	c.4936-86G>A		intron_variant		ENST00000682506.1
LOC105374076	XR_001740872.2	n.187-7536C>T		intron_variant, non_coding_transcript_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
KALRN	ENST00000682506.1	c.4936-86G>A		intron_variant			NM_001388419.1	A2

Frequencies

GnomAD3 genomes AF: 0.144 AC: 21628 AN: 150336 Hom.: 2481 Cov.: 32

Gnomad AFR AF: 0.112

Gnomad AMI AF: 0.105

Gnomad AMR AF: 0.274

Gnomad ASJ AF: 0.122

Gnomad EAS AF: 0.623

Gnomad SAS AF: 0.222

Gnomad FIN AF: 0.144

Gnomad MID AF: 0.228

Gnomad NFE AF: 0.0930

Gnomad OTH AF: 0.145

GnomAD4 exome AF: 0.112 AC: 114698 AN: 1024914 Hom.: 9786 Cov.: 16 AF XY: 0.115 AC XY: 56796 AN XY: 495470

Gnomad4 AFR exome AF: 0.110

Gnomad4 AMR exome AF: 0.376

Gnomad4 ASJ exome AF: 0.129

Gnomad4 EAS exome AF: 0.630

Gnomad4 SAS exome AF: 0.203

Gnomad4 FIN exome AF: 0.129

Gnomad4 NFE exome AF: 0.0882

Gnomad4 OTH exome AF: 0.141

GnomAD4 genome AF: 0.144 AC: 21667 AN: 150454 Hom.: 2493 Cov.: 32 AF XY: 0.155 AC XY: 11383 AN XY: 73334

Gnomad4 AFR AF: 0.113

Gnomad4 AMR AF: 0.275

Gnomad4 ASJ AF: 0.122

Gnomad4 EAS AF: 0.623

Gnomad4 SAS AF: 0.222

Gnomad4 FIN AF: 0.144

Gnomad4 NFE AF: 0.0930

Gnomad4 OTH AF: 0.149

Alfa AF: 0.107 Hom.: 1396

Bravo AF: 0.155

Asia WGS AF: 0.387 AC: 1342 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.92
CADD	Benign	0.63
DANN	Benign	0.35

Splicing

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

Publications

LitVar

Other links and lift over

dbSNP: rs2279784; hg19: chr3-124281604; COSMIC: COSV62566012;