chr3-124395138-T-G

Variant names:

• chr3-124395138-T-G
• rs13074913
• NM_001388419.1:c.1966T>G

Variant summary

Our verdict is Uncertain significance. The variant received 3 ACMG points: 3P and 0B. PM2 PP3

The NM_001388419.1(KALRN):​c.1966T>G​(p.Trp656Gly) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency: Genomes: not found (cov: 31)
• Consequence: KALRN NM_001388419.1 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 8.02
• 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 3 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.834

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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	KALRN	NM_001388419.1	MANE Select	c.1966T>G	p.Trp656Gly	missense	Exon 12 of 60	NP_001375348.1	O60229-7
	KALRN	NM_001024660.5		c.1960T>G	p.Trp654Gly	missense	Exon 12 of 60	NP_001019831.2	O60229-1
	KALRN	NM_001322988.2		c.1960T>G	p.Trp654Gly	missense	Exon 12 of 49	NP_001309917.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	KALRN	ENST00000682506.1	MANE Select	c.1966T>G	p.Trp656Gly	missense	Exon 12 of 60	ENSP00000508359.1	O60229-7
	KALRN	ENST00000240874.7	TSL:1	c.1960T>G	p.Trp654Gly	missense	Exon 12 of 34	ENSP00000240874.3	O60229-2
	KALRN	ENST00000460856.5	TSL:1	c.1960T>G	p.Trp654Gly	missense	Exon 12 of 34	ENSP00000418611.1	C9IZQ6

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 31

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.60
BayesDel_addAF	Pathogenic	0.32	D
BayesDel_noAF	Pathogenic	0.22
CADD	Pathogenic	29
DANN	Benign	0.96
DEOGEN2	Benign	0.078	T
Eigen	Uncertain	0.37
Eigen_PC	Uncertain	0.46
FATHMM_MKL	Uncertain	0.96	D
LIST_S2	Uncertain	0.95	D
M_CAP	Benign	0.049	D
MetaRNN	Pathogenic	0.83	D
MetaSVM	Benign	-0.56	T
MutationAssessor	Benign	2.0	M
PhyloP100		8.0
PrimateAI	Pathogenic	0.90	D
PROVEAN	Pathogenic	-6.8	D
REVEL	Uncertain	0.49
Sift	Benign	0.057	T
Sift4G	Benign	0.063	T
Polyphen		0.61	P
Vest4		0.79
MutPred		0.45		Loss of catalytic residue at M657 (P = 0.0055)
MVP		0.93
MPC		1.1
ClinPred		0.93	D
GERP RS		5.4
gMVP		0.78
Mutation Taster		=55/45	polymorphism

Splicing

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

Other links and lift over

dbSNP: rs13074913; hg19: chr3-124113985;