rs2272486

Positions:

• chr3-124269192-T-A
• chr3-124269192-T-C
• chr3-124269192-T-G

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 2P and 0B. PM2

The NM_001388419.1(KALRN):​c.906T>A​(p.His302Gln) variant causes a missense change involving the alteration of a non-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. Synonymous variant affecting the same amino acid position (i.e. H302H) 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: -1.68

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 2 ACMG points.

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

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
KALRN	NM_001388419.1	c.906T>A	p.His302Gln	missense_variant	5/60	ENST00000682506.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
KALRN	ENST00000682506.1	c.906T>A	p.His302Gln	missense_variant	5/60		NM_001388419.1	A2

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 56

GnomAD4 genome Cov.: 33

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.62
BayesDel_addAF	Benign	-0.0014	T
BayesDel_noAF	Benign	-0.24
CADD	Benign	3.9
DANN	Benign	0.80
DEOGEN2	Benign	0.079	T;.;T
Eigen	Benign	-1.0
Eigen_PC	Benign	-1.1
FATHMM_MKL	Benign	0.20	N
LIST_S2	Uncertain	0.91	D;D;D
M_CAP	Benign	0.024	T
MetaRNN	Uncertain	0.61	D;D;D
MetaSVM	Benign	-0.78	T
MutationAssessor	Benign	1.3	.;L;.
MutationTaster	Benign	0.021	P;P;P
PrimateAI	Pathogenic	0.90	D
PROVEAN	Pathogenic	-5.1	D;D;D
REVEL	Uncertain	0.31
Sift	Benign	0.52	T;T;T
Sift4G	Benign	0.63	T;T;T
Polyphen		0.23	B;B;.
Vest4		0.64
MutPred		0.28		Gain of MoRF binding (P = 0.088);Gain of MoRF binding (P = 0.088);Gain of MoRF binding (P = 0.088);
MVP		0.77
MPC		0.86
ClinPred		0.54	D
GERP RS		-5.8
gMVP		0.80

Splicing

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

Publications

LitVar

Other links and lift over

dbSNP: rs2272486; hg19: chr3-123988039;