NM_001388419.1:c.5090C>A

Variant names:

• chr3-124562997-C-A
• rs78202770
• NM_001388419.1:c.5090C>A

Variant summary

Our verdict is Benign. The variant received -14 ACMG points: 0P and 14B. 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
• Publications: 10 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]

LOC105374076 (HGNC:):

ACMG classification

Our verdict: Benign. The variant received -14 ACMG points.

• 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 VariationId 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 the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High AC in GnomAd4 at 1024 AD gene.

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

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	KALRN	NM_001388419.1	MANE Select	c.5090C>A	p.Pro1697Gln	missense	Exon 34 of 60	NP_001375348.1
	KALRN	NM_001024660.5		c.5084C>A	p.Pro1695Gln	missense	Exon 34 of 60	NP_001019831.2
	KALRN	NM_001322988.2		c.5084C>A	p.Pro1695Gln	missense	Exon 34 of 49	NP_001309917.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	KALRN	ENST00000682506.1	MANE Select	c.5090C>A	p.Pro1697Gln	missense	Exon 34 of 60	ENSP00000508359.1
	KALRN	ENST00000360013.7	TSL:5	c.5084C>A	p.Pro1695Gln	missense	Exon 34 of 60	ENSP00000353109.3
	KALRN	ENST00000354186.8	TSL:5	c.4988C>A	p.Pro1663Gln	missense	Exon 33 of 59	ENSP00000346122.4

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

GnomAD2 exomes AF: 0.00879 AC: 2187 AN: 248840 AF XY: 0.00908

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 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

African (AFR) AF: 0.000798 AC: 21 AN: 26300

American (AMR) AF: 0.00265 AC: 99 AN: 37290

Ashkenazi Jewish (ASJ) AF: 0.00266 AC: 45 AN: 16896

East Asian (EAS) AF: 0.0430 AC: 722 AN: 16808

South Asian (SAS) AF: 0.0103 AC: 856 AN: 83226

European-Finnish (FIN) AF: 0.0166 AC: 542 AN: 32578

Middle Eastern (MID) AF: 0.00358 AC: 16 AN: 4474

European-Non Finnish (NFE) AF: 0.00613 AC: 5851 AN: 953976

Other (OTH) AF: 0.00920 AC: 405 AN: 44028

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

African (AFR) AF: 0.00118 AC: 49 AN: 41578

American (AMR) AF: 0.00359 AC: 55 AN: 15306

Ashkenazi Jewish (ASJ) AF: 0.00288 AC: 10 AN: 3472

East Asian (EAS) AF: 0.0484 AC: 250 AN: 5170

South Asian (SAS) AF: 0.0116 AC: 56 AN: 4824

European-Finnish (FIN) AF: 0.0190 AC: 202 AN: 10616

Middle Eastern (MID) AF: 0.00340 AC: 1 AN: 294

European-Non Finnish (NFE) AF: 0.00569 AC: 387 AN: 68032

Other (OTH) AF: 0.00662 AC: 14 AN: 2114

Alfa AF: 0.00640 Hom.: 23

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

Feb 01, 2024

CeGaT Center for Human Genetics Tuebingen

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

KALRN: PP2, BS1, BS2

Computational scores

Source: dbNSFP v4.9

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
PhyloP100		7.9
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
Mutation Taster		=54/46	polymorphism

Splicing

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

Other links and lift over

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