rs13074913

chr3-124395138-T-G

Variant summary

Our verdict is Uncertain significance. Variant got 4 ACMG points: 4P and 0B. PM2 PP2 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

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

Verdict is Uncertain_significance. Variant got 4 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP2: Missense variant where missense usually causes diseases, KALRN
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.834

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
KALRN	NM_001388419.1	c.1966T>G	p.Trp656Gly	missense_variant	12/60	ENST00000682506.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
KALRN	ENST00000682506.1	c.1966T>G	p.Trp656Gly	missense_variant	12/60		NM_001388419.1	A2

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 31

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

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;.;T;.
Eigen	Uncertain	0.37
Eigen_PC	Uncertain	0.46
FATHMM_MKL	Uncertain	0.96	D
LIST_S2	Uncertain	0.95	D;D;D;D
M_CAP	Benign	0.049	D
MetaRNN	Pathogenic	0.83	D;D;D;D
MetaSVM	Benign	-0.56	T
MutationTaster	Benign	1.0	D;D;D
PrimateAI	Pathogenic	0.90	D
PROVEAN	Pathogenic	-6.8	D;D;D;D
REVEL	Uncertain	0.49
Sift	Benign	0.057	T;T;T;D
Sift4G	Benign	0.063	T;T;T;D
Polyphen		0.61	P;P;.;.
Vest4		0.79
MutPred		0.45		Loss of catalytic residue at M657 (P = 0.0055);Loss of catalytic residue at M657 (P = 0.0055);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

Splicing

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

Publications

LitVar

Other links and lift over

dbSNP: rs13074913; hg19: chr3-124113985;