rs2289843

Variant names:

• chr3-124477247-A-T
• rs2289843
• NM_001388419.1:c.4104A>T
• KALRN p.Ala1368Ala

Your query was ambiguous. Multiple possible variants found:

• chr3-124477247-A-T
• chr3-124477247-A-C

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Moderate BP6 BP7 BA1

The NM_001388419.1(KALRN):​c.4104A>T​(p.Ala1368Ala) variant causes a splice region, synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.132 in 1,607,274 control chromosomes in the GnomAD database, including 19,812 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (no stars).

• Frequency:
  • Genomes: 𝑓 0.12 (1918 hom., cov: 32)
  • Exomes 𝑓: 0.13 (17894 hom.)
• Consequence: KALRN NM_001388419.1 splice_region, synonymous
• Clinical Significance: Benign no assertion criteria provided B:1
• Conservation: PhyloP100: 0.948
• Publications: 17 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 -12 ACMG points.

• BP4: Computational evidence support a benign effect (REVEL=0.074).
• BP6: Variant 3-124477247-A-T is Benign according to our data. Variant chr3-124477247-A-T is described in ClinVar as Benign. ClinVar VariationId is 3060446.Status of the report is no_assertion_criteria_provided, 0 stars.
• BP7: Synonymous conserved (PhyloP=0.948 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.486 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001388419.1. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	KALRN	NM_001388419.1	MANE Select	c.4104A>T	p.Ala1368Ala	splice_region synonymous	Exon 27 of 60	NP_001375348.1	O60229-7
	KALRN	NM_001024660.5		c.4098A>T	p.Ala1366Ala	splice_region synonymous	Exon 27 of 60	NP_001019831.2	O60229-1
	KALRN	NM_001322988.2		c.4098A>T	p.Ala1366Ala	splice_region synonymous	Exon 27 of 49	NP_001309917.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	KALRN	ENST00000682506.1	MANE Select	c.4104A>T	p.Ala1368Ala	splice_region synonymous	Exon 27 of 60	ENSP00000508359.1	O60229-7
	KALRN	ENST00000240874.7	TSL:1	c.4098A>T	p.Ala1366Ala	splice_region synonymous	Exon 27 of 34	ENSP00000240874.3	O60229-2
	KALRN	ENST00000460856.5	TSL:1	c.4071A>T	p.Ala1357Ala	splice_region synonymous	Exon 27 of 34	ENSP00000418611.1	C9IZQ6

Frequencies

GnomAD3 genomes AF: 0.123 AC: 18652 AN: 152082 Hom.: 1907 Cov.: 32

Gnomad AFR AF: 0.0356

Gnomad AMI AF: 0.0932

Gnomad AMR AF: 0.224

Gnomad ASJ AF: 0.0568

Gnomad EAS AF: 0.502

Gnomad SAS AF: 0.174

Gnomad FIN AF: 0.209

Gnomad MID AF: 0.0510

Gnomad NFE AF: 0.111

Gnomad OTH AF: 0.114

GnomAD2 exomes AF: 0.172 AC: 43123 AN: 251102 AF XY: 0.165

Gnomad AFR exome AF: 0.0345

Gnomad AMR exome AF: 0.301

Gnomad ASJ exome AF: 0.0554

Gnomad EAS exome AF: 0.502

Gnomad FIN exome AF: 0.198

Gnomad NFE exome AF: 0.111

Gnomad OTH exome AF: 0.143

GnomAD4 exome AF: 0.133 AC: 193792 AN: 1455078 Hom.: 17894 Cov.: 29 AF XY: 0.132 AC XY: 95876 AN XY: 724346

African (AFR) AF: 0.0304 AC: 1013 AN: 33376

American (AMR) AF: 0.292 AC: 13057 AN: 44660

Ashkenazi Jewish (ASJ) AF: 0.0555 AC: 1450 AN: 26106

East Asian (EAS) AF: 0.539 AC: 21358 AN: 39632

South Asian (SAS) AF: 0.155 AC: 13360 AN: 86030

European-Finnish (FIN) AF: 0.193 AC: 10283 AN: 53402

Middle Eastern (MID) AF: 0.0620 AC: 357 AN: 5758

European-Non Finnish (NFE) AF: 0.113 AC: 125063 AN: 1105964

Other (OTH) AF: 0.131 AC: 7851 AN: 60150

GnomAD4 genome AF: 0.123 AC: 18668 AN: 152196 Hom.: 1918 Cov.: 32 AF XY: 0.132 AC XY: 9853 AN XY: 74408

African (AFR) AF: 0.0355 AC: 1477 AN: 41564

American (AMR) AF: 0.225 AC: 3431 AN: 15276

Ashkenazi Jewish (ASJ) AF: 0.0568 AC: 197 AN: 3470

East Asian (EAS) AF: 0.502 AC: 2594 AN: 5166

South Asian (SAS) AF: 0.173 AC: 837 AN: 4826

European-Finnish (FIN) AF: 0.209 AC: 2206 AN: 10576

Middle Eastern (MID) AF: 0.0445 AC: 13 AN: 292

European-Non Finnish (NFE) AF: 0.111 AC: 7578 AN: 68000

Other (OTH) AF: 0.118 AC: 250 AN: 2114

Alfa AF: 0.104 Hom.: 300

Bravo AF: 0.122

Asia WGS AF: 0.288 AC: 1002 AN: 3478

EpiCase AF: 0.107

EpiControl AF: 0.102

ClinVar

ClinVar submissions

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	-0.42
CADD	Benign	14
DANN	Benign	0.83
PhyloP100		0.95
Mutation Taster		=80/20	polymorphism (auto)

Splicing

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

MaxEntScan Visualizer can be used to analyze the impact of this mutation on the neighboring sequence.

Other links and lift over

dbSNP: rs2289843;

hg19: chr3-124196094;

COSMIC: COSV53756919;