chr3-124206748-T-A

Variant names:

• chr3-124206748-T-A
• rs6438833
• NM_001388419.1:c.74-21242T>A

Variant summary

Our verdict is Benign. The variant received -10 ACMG points: 0P and 10B. BP4_Moderate BA1

The NM_001388419.1(KALRN):​c.74-21242T>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0663 in 152,288 control chromosomes in the GnomAD database, including 308 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 0.066 (308 hom., cov: 33)
• Consequence: KALRN NM_001388419.1 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.601
• Publications: 5 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 -10 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.4).
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.0883 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001388419.1. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	KALRN	NM_001388419.1	MANE Select	c.74-21242T>A		intron	N/A	NP_001375348.1
	KALRN	NM_001024660.5		c.68-21242T>A		intron	N/A	NP_001019831.2
	KALRN	NM_001322988.2		c.68-21242T>A		intron	N/A	NP_001309917.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	KALRN	ENST00000682506.1	MANE Select	c.74-21242T>A		intron	N/A	ENSP00000508359.1
	KALRN	ENST00000240874.7	TSL:1	c.68-21242T>A		intron	N/A	ENSP00000240874.3
	KALRN	ENST00000460856.5	TSL:1	c.68-21242T>A		intron	N/A	ENSP00000418611.1

Frequencies

GnomAD3 genomes AF: 0.0664 AC: 10097 AN: 152170 Hom.: 309 Cov.: 33

Gnomad AFR AF: 0.0598

Gnomad AMI AF: 0.152

Gnomad AMR AF: 0.0695

Gnomad ASJ AF: 0.0652

Gnomad EAS AF: 0.0952

Gnomad SAS AF: 0.0737

Gnomad FIN AF: 0.0648

Gnomad MID AF: 0.0918

Gnomad NFE AF: 0.0656

Gnomad OTH AF: 0.0765

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

GnomAD4 genome AF: 0.0663 AC: 10101 AN: 152288 Hom.: 308 Cov.: 33 AF XY: 0.0671 AC XY: 5001 AN XY: 74482

African (AFR) AF: 0.0598 AC: 2484 AN: 41560

American (AMR) AF: 0.0695 AC: 1063 AN: 15304

Ashkenazi Jewish (ASJ) AF: 0.0652 AC: 226 AN: 3466

East Asian (EAS) AF: 0.0953 AC: 494 AN: 5186

South Asian (SAS) AF: 0.0736 AC: 355 AN: 4824

European-Finnish (FIN) AF: 0.0648 AC: 687 AN: 10610

Middle Eastern (MID) AF: 0.0884 AC: 26 AN: 294

European-Non Finnish (NFE) AF: 0.0656 AC: 4461 AN: 68018

Other (OTH) AF: 0.0785 AC: 166 AN: 2114

Alfa AF: 0.0589 Hom.: 28

Bravo AF: 0.0661

Asia WGS AF: 0.0890 AC: 308 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.40
CADD	Benign	11
DANN	Benign	0.74
PhyloP100		0.60
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: rs6438833; hg19: chr3-123925595;