rs74389479

Variant names:

• chr3-124477314-C-A
• rs74389479
• NM_001388419.1:c.4171C>A

Variant summary

Our verdict is Uncertain significance. The variant received 2 ACMG points: 2P and 0B. PM2

The ENST00000682506.1(KALRN):​c.4171C>A​(p.His1391Asn) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency: Genomes: not found (cov: 33)
• Consequence: KALRN ENST00000682506.1 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 7.91
• Publications: 1 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: Uncertain_significance. The variant received 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

Variant Effect in Transcripts

ACMG analysis was done for transcript: ENST00000682506.1. 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.4171C>A	p.His1391Asn	missense	Exon 27 of 60	NP_001375348.1
	KALRN	NM_001024660.5		c.4165C>A	p.His1389Asn	missense	Exon 27 of 60	NP_001019831.2
	KALRN	NM_001322988.2		c.4165C>A	p.His1389Asn	missense	Exon 27 of 49	NP_001309917.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	KALRN	ENST00000682506.1	MANE Select	c.4171C>A	p.His1391Asn	missense	Exon 27 of 60	ENSP00000508359.1
	KALRN	ENST00000240874.7	TSL:1	c.4165C>A	p.His1389Asn	missense	Exon 27 of 34	ENSP00000240874.3
	KALRN	ENST00000460856.5	TSL:1	c.4138C>A	p.His1380Asn	missense	Exon 27 of 34	ENSP00000418611.1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 30

GnomAD4 genome Cov.: 33

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.13
BayesDel_addAF	Uncertain	0.099	D
BayesDel_noAF	Benign	-0.090
CADD	Pathogenic	26
DANN	Uncertain	0.99
DEOGEN2	Benign	0.085	T
Eigen	Uncertain	0.49
Eigen_PC	Uncertain	0.56
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Uncertain	0.94	D
M_CAP	Benign	0.023	T
MetaRNN	Uncertain	0.43	T
MetaSVM	Benign	-0.48	T
MutationAssessor	Uncertain	2.1	M
PhyloP100		7.9
PrimateAI	Pathogenic	0.85	D
PROVEAN	Pathogenic	-5.5	D
REVEL	Uncertain	0.29
Sift	Uncertain	0.0020	D
Sift4G	Uncertain	0.0090	D
Polyphen		0.48	P
Vest4		0.53
MutPred		0.55		Gain of relative solvent accessibility (P = 0.1259)
MVP		0.59
MPC		1.2
ClinPred		0.99	D
GERP RS		5.2
gMVP		0.64
Mutation Taster		=41/59	disease causing

Splicing

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

Other links and lift over

dbSNP: rs74389479; hg19: chr3-124196161;