chr3-124334472-G-C

Variant names:

• chr3-124334472-G-C
• rs1056310843
• NM_001388419.1:c.1624G>C

Variant summary

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

The NM_001388419.1(KALRN):​c.1624G>C​(p.Val542Leu) 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. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. V542I) has been classified as Benign.

• Frequency: Genomes: not found (cov: 33)
• Consequence: KALRN NM_001388419.1 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 10.0
• Publications: 0 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

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
KALRN	NM_001388419.1	c.1624G>C	p.Val542Leu	missense_variant	Exon 9 of 60	ENST00000682506.1	NP_001375348.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
KALRN	ENST00000682506.1	c.1624G>C	p.Val542Leu	missense_variant	Exon 9 of 60		NM_001388419.1	ENSP00000508359.1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 33

Alfa AF: 0.00 Hom.: 0

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.94
BayesDel_addAF	Uncertain	0.087	D
BayesDel_noAF	Benign	-0.11
CADD	Pathogenic	29
DANN	Benign	0.82
DEOGEN2	Benign	0.0065	T;.;T;.
Eigen	Uncertain	0.42
Eigen_PC	Uncertain	0.52
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Pathogenic	0.97	D;D;D;D
M_CAP	Benign	0.026	D
MetaRNN	Uncertain	0.55	D;D;D;D
MetaSVM	Benign	-0.96	T
MutationAssessor	Benign	0.30	.;N;.;.
PhyloP100		10
PrimateAI	Pathogenic	0.90	D
PROVEAN	Benign	-0.65	N;N;N;N
REVEL	Benign	0.26
Sift	Benign	1.0	T;T;T;T
Sift4G	Benign	1.0	T;T;T;T
Polyphen		0.98	D;D;.;.
Vest4		0.58
MutPred		0.50		Loss of MoRF binding (P = 0.0951);Loss of MoRF binding (P = 0.0951);Loss of MoRF binding (P = 0.0951);.;
MVP		0.79
MPC		0.63
ClinPred		0.50	D
GERP RS		5.3
PromoterAI		-0.016	Neutral
gMVP		0.41
Mutation Taster		=46/54	disease causing

Splicing

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

Other links and lift over

dbSNP: rs1056310843; hg19: chr3-124053319;