rs61745397

Positions:

• chr3-124398710-T-A

Variant summary

Our verdict is Benign. Variant got -7 ACMG points: 1P and 8B. PP2 BP4_Strong BS2

The NM_001388419.1(KALRN):​c.2185T>A​(p.Ser729Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00388 in 1,614,082 control chromosomes in the GnomAD database, including 12 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.

• Frequency:
  • Genomes: 𝑓 0.0029 (0 hom., cov: 32)
  • Exomes 𝑓: 0.0040 (12 hom.)
• Consequence: KALRN NM_001388419.1 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 3.23

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

Verdict is Benign. Variant got -7 ACMG points.

• PP2: Missense variant where missense usually causes diseases, KALRN
• BP4: Computational evidence support a benign effect (MetaRNN=0.0060512125).
• BS2: High AC in GnomAd4 at 444 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
KALRN	NM_001388419.1	c.2185T>A	p.Ser729Thr	missense_variant	13/60	ENST00000682506.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
KALRN	ENST00000682506.1	c.2185T>A	p.Ser729Thr	missense_variant	13/60		NM_001388419.1	A2

Frequencies

GnomAD3 genomes AF: 0.00292 AC: 444 AN: 152090 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.000845

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000786

Gnomad ASJ AF: 0.00173

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.0113

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00391

Gnomad OTH AF: 0.00239

GnomAD3 exomes AF: 0.00266 AC: 669 AN: 251310 Hom.: 0 AF XY: 0.00248 AC XY: 337 AN XY: 135826

Gnomad AFR exome AF: 0.000554

Gnomad AMR exome AF: 0.000376

Gnomad ASJ exome AF: 0.00189

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00836

Gnomad NFE exome AF: 0.00381

Gnomad OTH exome AF: 0.00228

GnomAD4 exome AF: 0.00398 AC: 5825 AN: 1461874 Hom.: 12 Cov.: 31 AF XY: 0.00373 AC XY: 2710 AN XY: 727236

Gnomad4 AFR exome AF: 0.000538

Gnomad4 AMR exome AF: 0.000470

Gnomad4 ASJ exome AF: 0.00172

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00829

Gnomad4 NFE exome AF: 0.00464

Gnomad4 OTH exome AF: 0.00225

GnomAD4 genome AF: 0.00292 AC: 444 AN: 152208 Hom.: 0 Cov.: 32 AF XY: 0.00310 AC XY: 231 AN XY: 74424

Gnomad4 AFR AF: 0.000843

Gnomad4 AMR AF: 0.000785

Gnomad4 ASJ AF: 0.00173

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.0113

Gnomad4 NFE AF: 0.00391

Gnomad4 OTH AF: 0.00237

Alfa AF: 0.00288 Hom.: 0

Bravo AF: 0.00202

TwinsUK AF: 0.00458 AC: 17

ALSPAC AF: 0.00597 AC: 23

ESP6500AA AF: 0.000454 AC: 2

ESP6500EA AF: 0.00279 AC: 24

ExAC AF: 0.00294 AC: 357

EpiCase AF: 0.00213

EpiControl AF: 0.00314

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.069
BayesDel_addAF	Benign	-0.49	T
BayesDel_noAF	Benign	-0.48
CADD	Uncertain	24
DANN	Uncertain	0.99
DEOGEN2	Benign	0.020	T;.;T
Eigen	Benign	-0.038
Eigen_PC	Benign	0.080
FATHMM_MKL	Uncertain	0.95	D
LIST_S2	Uncertain	0.92	D;D;D
M_CAP	Benign	0.029	D
MetaRNN	Benign	0.0061	T;T;T
MetaSVM	Benign	-0.91	T
MutationTaster	Benign	0.96	D;D;D
PrimateAI	Uncertain	0.59	T
PROVEAN	Benign	-1.6	N;N;N
REVEL	Benign	0.023
Sift	Benign	0.16	T;T;T
Sift4G	Benign	0.31	T;T;T
Polyphen		0.78	P;P;.
Vest4		0.33
MVP		0.70
MPC		0.59
ClinPred		0.010	T
GERP RS		4.3
gMVP		0.28

Splicing

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

Publications

LitVar

Other links and lift over

dbSNP: rs61745397; hg19: chr3-124117557;