rs78202770

chr3-124562997-C-Achr3-124562997-C-T

Variant summary

Our verdict is Benign. Variant got -13 ACMG points: 1P and 14B. PP2 BP4_Strong BP6_Moderate BS1 BS2

The NM_001388419.1(KALRN):c.5090C>A(p.Pro1697Gln) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.007 in 1,367,892 control chromosomes in the GnomAD database, including 66 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

• Frequency:
  • Genomes: 𝑓 0.0067 (14 hom., cov: 32)
  • Exomes 𝑓: 0.0070 (52 hom.)
• Consequence: KALRN NM_001388419.1 missense
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 7.91

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]

LOC105374076 (HGNC:):

ACMG classification

Verdict is Benign. Variant got -13 ACMG points.

• PP2: Missense variant where missense usually causes diseases, KALRN
• BP4: Computational evidence support a benign effect (MetaRNN=0.005629152).
• BP6: Variant 3-124562997-C-A is Benign according to our data. Variant chr3-124562997-C-A is described in ClinVar as [Benign]. Clinvar id is 3024845.Status of the report is criteria_provided_single_submitter, 1 stars.
• BS1: Variant frequency is greater than expected in population eas. gnomad4 allele frequency = 0.00672 (1024/152316) while in subpopulation EAS AF= 0.0484 (250/5170). AF 95% confidence interval is 0.0434. There are 14 homozygotes in gnomad4. There are 559 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.
• BS2: High AC in GnomAd at 1021 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
KALRN	NM_001388419.1	c.5090C>A	p.Pro1697Gln	missense_variant	34/60	ENST00000682506.1
LOC105374076	XR_001740872.2	n.187-7776G>T		intron_variant, non_coding_transcript_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
KALRN	ENST00000682506.1	c.5090C>A	p.Pro1697Gln	missense_variant	34/60		NM_001388419.1	A2

Frequencies

GnomAD3 genomes AF: 0.00671 AC: 1021 AN: 152198 Hom.: 14 Cov.: 32

Gnomad AFR AF: 0.00118

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00360

Gnomad ASJ AF: 0.00288

Gnomad EAS AF: 0.0482

Gnomad SAS AF: 0.0114

Gnomad FIN AF: 0.0190

Gnomad MID AF: 0.00316

Gnomad NFE AF: 0.00569

Gnomad OTH AF: 0.00574

GnomAD3 exomes AF: 0.00879 AC: 2187 AN: 248840 Hom.: 20 AF XY: 0.00908 AC XY: 1227 AN XY: 135190

Gnomad AFR exome AF: 0.000780

Gnomad AMR exome AF: 0.00258

Gnomad ASJ exome AF: 0.00249

Gnomad EAS exome AF: 0.0396

Gnomad SAS exome AF: 0.0117

Gnomad FIN exome AF: 0.0167

Gnomad NFE exome AF: 0.00510

Gnomad OTH exome AF: 0.00942

GnomAD4 exome AF: 0.00704 AC: 8557 AN: 1215576 Hom.: 52 Cov.: 30 AF XY: 0.00714 AC XY: 4302 AN XY: 602448

Gnomad4 AFR exome AF: 0.000798

Gnomad4 AMR exome AF: 0.00265

Gnomad4 ASJ exome AF: 0.00266

Gnomad4 EAS exome AF: 0.0430

Gnomad4 SAS exome AF: 0.0103

Gnomad4 FIN exome AF: 0.0166

Gnomad4 NFE exome AF: 0.00613

Gnomad4 OTH exome AF: 0.00920

GnomAD4 genome AF: 0.00672 AC: 1024 AN: 152316 Hom.: 14 Cov.: 32 AF XY: 0.00751 AC XY: 559 AN XY: 74466

Gnomad4 AFR AF: 0.00118

Gnomad4 AMR AF: 0.00359

Gnomad4 ASJ AF: 0.00288

Gnomad4 EAS AF: 0.0484

Gnomad4 SAS AF: 0.0116

Gnomad4 FIN AF: 0.0190

Gnomad4 NFE AF: 0.00569

Gnomad4 OTH AF: 0.00662

Alfa AF: 0.00629 Hom.: 11

Bravo AF: 0.00526

TwinsUK AF: 0.00701 AC: 26

ALSPAC AF: 0.00571 AC: 22

ESP6500AA AF: 0.00121 AC: 5

ESP6500EA AF: 0.00583 AC: 49

ExAC AF: 0.00836 AC: 1012

Asia WGS AF: 0.0410 AC: 143 AN: 3478

EpiCase AF: 0.00518

EpiControl AF: 0.00616

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Benign:1

Benign, criteria provided, single submitter

clinical testing

CeGaT Center for Human Genetics Tuebingen

Feb 01, 2024

KALRN: PP2, BS1, BS2 -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.27
BayesDel_addAF	Benign	-0.22	T
BayesDel_noAF	Uncertain	-0.060
Cadd	Uncertain	24
Dann	Uncertain	0.99
DEOGEN2	Benign	0.068	T
Eigen	Uncertain	0.22
Eigen_PC	Benign	0.19
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Pathogenic	0.99	D
MetaRNN	Benign	0.0056	T
MetaSVM	Benign	-0.78	T
MutationTaster	Benign	1.0	D;D
PrimateAI	Uncertain	0.69	T
PROVEAN	Uncertain	-4.1	D
REVEL	Uncertain	0.30
Sift	Uncertain	0.0070	D
Sift4G	Benign	0.088	T
Vest4		0.72
MVP		0.80
ClinPred		0.017	T
GERP RS		4.5

Splicing

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

Publications

LitVar

Other links and lift over

dbSNP: rs78202770; hg19: chr3-124281844; COSMIC: COSV62558449;