chr3-124347254-G-C

Variant names:

• chr3-124347254-G-C
• rs61746078
• NM_001388419.1:c.1759G>C

Variant summary

Our verdict is Uncertain significance. The variant received 1 ACMG points: 2P and 1B. PM2 BP4

The NM_001388419.1(KALRN):​c.1759G>C​(p.Glu587Gln) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000067 in 149,182 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency: Genomes: 𝑓 0.0000067 (0 hom., cov: 32)
• Consequence: KALRN NM_001388419.1 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 10.0
• 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 1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.34728944).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
KALRN	NM_001388419.1	c.1759G>C	p.Glu587Gln	missense_variant	Exon 10 of 60	ENST00000682506.1	NP_001375348.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
KALRN	ENST00000682506.1	c.1759G>C	p.Glu587Gln	missense_variant	Exon 10 of 60		NM_001388419.1	ENSP00000508359.1

Frequencies

GnomAD3 genomes AF: 0.00000670 AC: 1 AN: 149182 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000148

Gnomad OTH AF: 0.00

GnomAD4 exome Cov.: 32

GnomAD4 genome AF: 0.00000670 AC: 1 AN: 149182 Hom.: 0 Cov.: 32 AF XY: 0.00 AC XY: 0 AN XY: 72586

African (AFR) AF: 0.00 AC: 0 AN: 40352

American (AMR) AF: 0.00 AC: 0 AN: 14868

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3454

East Asian (EAS) AF: 0.00 AC: 0 AN: 4878

South Asian (SAS) AF: 0.00 AC: 0 AN: 4674

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10034

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 308

European-Non Finnish (NFE) AF: 0.0000148 AC: 1 AN: 67666

Other (OTH) AF: 0.00 AC: 0 AN: 2040

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.00000378

ExAC AF: 0.00000824 AC: 1

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.73
BayesDel_addAF	Benign	-0.046	T
BayesDel_noAF	Benign	-0.30
CADD	Pathogenic	29
DANN	Uncertain	0.98
DEOGEN2	Benign	0.017	T;.;T;.
Eigen	Uncertain	0.40
Eigen_PC	Uncertain	0.53
FATHMM_MKL	Uncertain	0.95	D
LIST_S2	Uncertain	0.96	D;D;D;D
M_CAP	Benign	0.016	T
MetaRNN	Benign	0.35	T;T;T;T
MetaSVM	Benign	-0.93	T
MutationAssessor	Benign	0.29	.;N;.;.
PhyloP100		10
PrimateAI	Pathogenic	0.86	D
PROVEAN	Benign	-1.4	N;N;N;N
REVEL	Benign	0.22
Sift	Benign	0.49	T;T;T;T
Sift4G	Benign	0.35	T;T;T;T
Polyphen		0.025	B;B;.;.
Vest4		0.34
MutPred		0.39		Gain of glycosylation at T590 (P = 0.0483);Gain of glycosylation at T590 (P = 0.0483);Gain of glycosylation at T590 (P = 0.0483);.;
MVP		0.47
MPC		0.64
ClinPred		0.63	D
GERP RS		5.3
gMVP		0.43
Mutation Taster		=60/40	polymorphism

Splicing

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

Other links and lift over

dbSNP: rs61746078; hg19: chr3-124066101;