3-124269192-T-C

Variant names:

• chr3-124269192-T-C
• rs2272486
• NM_001388419.1:c.906T>C

Variant summary

Our verdict is Benign. The variant received -10 ACMG points: 0P and 10B. BP6 BP7 BA1

The NM_001024660.5(KALRN):​c.900T>C​(p.His300His) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.617 in 1,610,832 control chromosomes in the GnomAD database, including 307,770 homozygotes. Variant has been reported in ClinVar as Benign (no stars).

• Frequency:
  • Genomes: 𝑓 0.62 (29775 hom., cov: 33)
  • Exomes 𝑓: 0.62 (277995 hom.)
• Consequence: KALRN NM_001024660.5 synonymous
• Clinical Significance: Benign no assertion criteria provided B:1
• Conservation: PhyloP100: -1.68
• Publications: 14 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: Benign. The variant received -10 ACMG points.

• BP6: Variant 3-124269192-T-C is Benign according to our data. Variant chr3-124269192-T-C is described in ClinVar as Benign. ClinVar VariationId is 3060559.Status of the report is no_assertion_criteria_provided, 0 stars.
• BP7: Synonymous conserved (PhyloP=-1.68 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (AMR) allele frequency at 95% confidence interval = 0.649 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001024660.5. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	KALRN	NM_001388419.1	MANE Select	c.906T>C	p.His302His	synonymous	Exon 5 of 60	NP_001375348.1
	KALRN	NM_001024660.5		c.900T>C	p.His300His	synonymous	Exon 5 of 60	NP_001019831.2
	KALRN	NM_001322988.2		c.900T>C	p.His300His	synonymous	Exon 5 of 49	NP_001309917.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	KALRN	ENST00000682506.1	MANE Select	c.906T>C	p.His302His	synonymous	Exon 5 of 60	ENSP00000508359.1
	KALRN	ENST00000240874.7	TSL:1	c.900T>C	p.His300His	synonymous	Exon 5 of 34	ENSP00000240874.3
	KALRN	ENST00000460856.5	TSL:1	c.900T>C	p.His300His	synonymous	Exon 5 of 34	ENSP00000418611.1

Frequencies

GnomAD3 genomes AF: 0.624 AC: 94847 AN: 151984 Hom.: 29745 Cov.: 33

Gnomad AFR AF: 0.649

Gnomad AMI AF: 0.548

Gnomad AMR AF: 0.659

Gnomad ASJ AF: 0.569

Gnomad EAS AF: 0.537

Gnomad SAS AF: 0.628

Gnomad FIN AF: 0.602

Gnomad MID AF: 0.601

Gnomad NFE AF: 0.614

Gnomad OTH AF: 0.658

GnomAD2 exomes AF: 0.620 AC: 154702 AN: 249586 AF XY: 0.617

Gnomad AFR exome AF: 0.648

Gnomad AMR exome AF: 0.686

Gnomad ASJ exome AF: 0.576

Gnomad EAS exome AF: 0.538

Gnomad FIN exome AF: 0.610

Gnomad NFE exome AF: 0.612

Gnomad OTH exome AF: 0.620

GnomAD4 exome AF: 0.617 AC: 899517 AN: 1458730 Hom.: 277995 Cov.: 56 AF XY: 0.616 AC XY: 446472 AN XY: 725092

African (AFR) AF: 0.655 AC: 21880 AN: 33420

American (AMR) AF: 0.684 AC: 30566 AN: 44668

Ashkenazi Jewish (ASJ) AF: 0.579 AC: 15127 AN: 26118

East Asian (EAS) AF: 0.508 AC: 20138 AN: 39614

South Asian (SAS) AF: 0.624 AC: 53801 AN: 86214

European-Finnish (FIN) AF: 0.600 AC: 31729 AN: 52890

Middle Eastern (MID) AF: 0.587 AC: 3277 AN: 5586

European-Non Finnish (NFE) AF: 0.618 AC: 685445 AN: 1109998

Other (OTH) AF: 0.624 AC: 37554 AN: 60222

GnomAD4 genome AF: 0.624 AC: 94934 AN: 152102 Hom.: 29775 Cov.: 33 AF XY: 0.623 AC XY: 46317 AN XY: 74360

African (AFR) AF: 0.649 AC: 26953 AN: 41506

American (AMR) AF: 0.660 AC: 10083 AN: 15288

Ashkenazi Jewish (ASJ) AF: 0.569 AC: 1975 AN: 3470

East Asian (EAS) AF: 0.537 AC: 2770 AN: 5156

South Asian (SAS) AF: 0.627 AC: 3022 AN: 4820

European-Finnish (FIN) AF: 0.602 AC: 6365 AN: 10574

Middle Eastern (MID) AF: 0.616 AC: 181 AN: 294

European-Non Finnish (NFE) AF: 0.614 AC: 41705 AN: 67976

Other (OTH) AF: 0.655 AC: 1382 AN: 2110

Alfa AF: 0.615 Hom.: 71694

Bravo AF: 0.632

Asia WGS AF: 0.631 AC: 2195 AN: 3478

EpiCase AF: 0.617

EpiControl AF: 0.619

ClinVar

ClinVar submissions as Germline

Significance: Benign

Revision: no assertion criteria provided

Pathogenic	VUS	Benign	Condition
-	-	1	KALRN-related disorder (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.63
CADD	Benign	0.19
DANN	Benign	0.51
PhyloP100		-1.7
Mutation Taster		=100/0	polymorphism (auto)

Splicing

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

Other links and lift over

dbSNP: rs2272486; hg19: chr3-123988039; COSMIC: COSV53774804; COSMIC: COSV53774804;