3-124667095-T-C

Variant names:

• chr3-124667095-T-C
• rs2289420
• NM_001388419.1:c.6615T>C
• KALRN p.Val2205Val

Variant summary

Our verdict is Benign. The variant received -11 ACMG points: 0P and 11B. BP4_Moderate BP7 BA1

The NM_001388419.1(KALRN):​c.6615T>C​(p.Val2205Val) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0274 in 1,613,910 control chromosomes in the GnomAD database, including 834 homozygotes. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Synonymous variant affecting the same amino acid position (i.e. V2205V) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.028 (81 hom., cov: 32)
  • Exomes 𝑓: 0.027 (753 hom.)
• Consequence: KALRN NM_001388419.1 synonymous
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.0870
• Publications: 7 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 -11 ACMG points.

• BP4: Computational evidence support a benign effect (REVEL=0.041).
• BP7: Synonymous conserved (PhyloP=-0.087 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.0725 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.6615T>C	p.Val2205Val	synonymous	Exon 47 of 60	NP_001375348.1	O60229-7
	KALRN	NM_001024660.5		c.6612T>C	p.Val2204Val	synonymous	Exon 47 of 60	NP_001019831.2	O60229-1
	KALRN	NM_001322988.2		c.6609T>C	p.Val2203Val	synonymous	Exon 47 of 49	NP_001309917.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	KALRN	ENST00000682506.1	MANE Select	c.6615T>C	p.Val2205Val	synonymous	Exon 47 of 60	ENSP00000508359.1	O60229-7
	KALRN	ENST00000291478.9	TSL:1	c.1521T>C	p.Val507Val	synonymous	Exon 14 of 27	ENSP00000291478.4	O60229-4
	KALRN	ENST00000360013.7	TSL:5	c.6612T>C	p.Val2204Val	synonymous	Exon 47 of 60	ENSP00000353109.3	O60229-1

Frequencies

GnomAD3 genomes AF: 0.0277 AC: 4222 AN: 152208 Hom.: 79 Cov.: 32

Gnomad AFR AF: 0.0274

Gnomad AMI AF: 0.0164

Gnomad AMR AF: 0.0401

Gnomad ASJ AF: 0.0216

Gnomad EAS AF: 0.0784

Gnomad SAS AF: 0.0456

Gnomad FIN AF: 0.00847

Gnomad MID AF: 0.0253

Gnomad NFE AF: 0.0237

Gnomad OTH AF: 0.0220

GnomAD2 exomes AF: 0.0318 AC: 7986 AN: 251264 AF XY: 0.0313

Gnomad AFR exome AF: 0.0257

Gnomad AMR exome AF: 0.0482

Gnomad ASJ exome AF: 0.0185

Gnomad EAS exome AF: 0.0891

Gnomad FIN exome AF: 0.00776

Gnomad NFE exome AF: 0.0214

Gnomad OTH exome AF: 0.0279

GnomAD4 exome AF: 0.0273 AC: 39941 AN: 1461584 Hom.: 753 Cov.: 31 AF XY: 0.0274 AC XY: 19912 AN XY: 727086

African (AFR) AF: 0.0261 AC: 873 AN: 33472

American (AMR) AF: 0.0496 AC: 2218 AN: 44698

Ashkenazi Jewish (ASJ) AF: 0.0168 AC: 438 AN: 26134

East Asian (EAS) AF: 0.0956 AC: 3793 AN: 39676

South Asian (SAS) AF: 0.0438 AC: 3776 AN: 86162

European-Finnish (FIN) AF: 0.00837 AC: 447 AN: 53416

Middle Eastern (MID) AF: 0.0121 AC: 70 AN: 5768

European-Non Finnish (NFE) AF: 0.0238 AC: 26455 AN: 1111870

Other (OTH) AF: 0.0310 AC: 1871 AN: 60388

GnomAD4 genome AF: 0.0278 AC: 4241 AN: 152326 Hom.: 81 Cov.: 32 AF XY: 0.0280 AC XY: 2089 AN XY: 74490

African (AFR) AF: 0.0274 AC: 1140 AN: 41582

American (AMR) AF: 0.0406 AC: 621 AN: 15298

Ashkenazi Jewish (ASJ) AF: 0.0216 AC: 75 AN: 3472

East Asian (EAS) AF: 0.0788 AC: 408 AN: 5180

South Asian (SAS) AF: 0.0460 AC: 222 AN: 4824

European-Finnish (FIN) AF: 0.00847 AC: 90 AN: 10626

Middle Eastern (MID) AF: 0.0238 AC: 7 AN: 294

European-Non Finnish (NFE) AF: 0.0237 AC: 1612 AN: 68024

Other (OTH) AF: 0.0241 AC: 51 AN: 2114

Alfa AF: 0.0243 Hom.: 79

Bravo AF: 0.0299

Asia WGS AF: 0.0560 AC: 194 AN: 3478

EpiCase AF: 0.0236

EpiControl AF: 0.0202

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.54
CADD	Benign	5.8
DANN	Benign	0.74
PhyloP100		-0.087
Mutation Taster		=100/0	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: rs2289420;

hg19: chr3-124385942;

COSMIC: COSV52260007;