3-124462892-G-A

Variant names:

• chr3-124462892-G-A
• rs2289840
• NM_001388419.1:c.4031+259G>A

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_001388419.1(KALRN):​c.4031+259G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.305 in 152,076 control chromosomes in the GnomAD database, including 7,759 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 0.31 (7759 hom., cov: 33)
• Consequence: KALRN NM_001388419.1 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.665
• Publications: 2 publications found

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

Our verdict: Benign. The variant received -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.83).
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.579 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
KALRN	NM_001388419.1	c.4031+259G>A		intron_variant	Intron 25 of 59	ENST00000682506.1	NP_001375348.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
KALRN	ENST00000682506.1	c.4031+259G>A		intron_variant	Intron 25 of 59		NM_001388419.1	ENSP00000508359.1

Frequencies

GnomAD3 genomes AF: 0.305 AC: 46353 AN: 151958 Hom.: 7744 Cov.: 33

Gnomad AFR AF: 0.224

Gnomad AMI AF: 0.208

Gnomad AMR AF: 0.384

Gnomad ASJ AF: 0.261

Gnomad EAS AF: 0.597

Gnomad SAS AF: 0.353

Gnomad FIN AF: 0.408

Gnomad MID AF: 0.222

Gnomad NFE AF: 0.300

Gnomad OTH AF: 0.293

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

GnomAD4 genome AF: 0.305 AC: 46386 AN: 152076 Hom.: 7759 Cov.: 33 AF XY: 0.315 AC XY: 23394 AN XY: 74332

African (AFR) AF: 0.223 AC: 9263 AN: 41476

American (AMR) AF: 0.384 AC: 5873 AN: 15280

Ashkenazi Jewish (ASJ) AF: 0.261 AC: 907 AN: 3472

East Asian (EAS) AF: 0.597 AC: 3090 AN: 5176

South Asian (SAS) AF: 0.353 AC: 1704 AN: 4828

European-Finnish (FIN) AF: 0.408 AC: 4310 AN: 10562

Middle Eastern (MID) AF: 0.228 AC: 67 AN: 294

European-Non Finnish (NFE) AF: 0.300 AC: 20360 AN: 67972

Other (OTH) AF: 0.296 AC: 623 AN: 2106

Alfa AF: 0.299 Hom.: 22402

Bravo AF: 0.298

Asia WGS AF: 0.439 AC: 1524 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.83
CADD	Benign	1.4
DANN	Benign	0.37
PhyloP100		-0.67
Mutation Taster		=100/0	polymorphism (auto)

Splicing

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

Other links and lift over

dbSNP: rs2289840; hg19: chr3-124181739;