NM_001388419.1:c.2185T>A

Variant names:

• chr3-124398710-T-A
• rs61745397
• NM_001388419.1:c.2185T>A

Variant summary

Our verdict is Benign. The variant received -8 ACMG points: 0P and 8B. 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
• Publications: 5 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 -8 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0060512125).
• BS2: High AC in GnomAd4 at 444 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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	KALRN	NM_001388419.1	MANE Select	c.2185T>A	p.Ser729Thr	missense	Exon 13 of 60	NP_001375348.1	O60229-7
	KALRN	NM_001024660.5		c.2179T>A	p.Ser727Thr	missense	Exon 13 of 60	NP_001019831.2	O60229-1
	KALRN	NM_001322988.2		c.2179T>A	p.Ser727Thr	missense	Exon 13 of 49	NP_001309917.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	KALRN	ENST00000682506.1	MANE Select	c.2185T>A	p.Ser729Thr	missense	Exon 13 of 60	ENSP00000508359.1	O60229-7
	KALRN	ENST00000240874.7	TSL:1	c.2179T>A	p.Ser727Thr	missense	Exon 13 of 34	ENSP00000240874.3	O60229-2
	KALRN	ENST00000460856.5	TSL:1	c.2179T>A	p.Ser727Thr	missense	Exon 13 of 34	ENSP00000418611.1	C9IZQ6

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

GnomAD2 exomes AF: 0.00266 AC: 669 AN: 251310 AF XY: 0.00248

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 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

African (AFR) AF: 0.000538 AC: 18 AN: 33480

American (AMR) AF: 0.000470 AC: 21 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.00172 AC: 45 AN: 26136

East Asian (EAS) AF: 0.00 AC: 0 AN: 39700

South Asian (SAS) AF: 0.00 AC: 0 AN: 86258

European-Finnish (FIN) AF: 0.00829 AC: 443 AN: 53410

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5768

European-Non Finnish (NFE) AF: 0.00464 AC: 5162 AN: 1112004

Other (OTH) AF: 0.00225 AC: 136 AN: 60394

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

African (AFR) AF: 0.000843 AC: 35 AN: 41530

American (AMR) AF: 0.000785 AC: 12 AN: 15292

Ashkenazi Jewish (ASJ) AF: 0.00173 AC: 6 AN: 3468

East Asian (EAS) AF: 0.00 AC: 0 AN: 5170

South Asian (SAS) AF: 0.00 AC: 0 AN: 4816

European-Finnish (FIN) AF: 0.0113 AC: 120 AN: 10604

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.00391 AC: 266 AN: 68012

Other (OTH) AF: 0.00237 AC: 5 AN: 2110

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 v4.9

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
Eigen	Benign	-0.038
Eigen_PC	Benign	0.080
FATHMM_MKL	Uncertain	0.95	D
LIST_S2	Uncertain	0.92	D
M_CAP	Benign	0.029	D
MetaRNN	Benign	0.0061	T
MetaSVM	Benign	-0.91	T
MutationAssessor	Uncertain	2.2	M
PhyloP100		3.2
PrimateAI	Uncertain	0.59	T
PROVEAN	Benign	-1.6	N
REVEL	Benign	0.023
Sift	Benign	0.16	T
Sift4G	Benign	0.31	T
Polyphen		0.78	P
Vest4		0.33
MVP		0.70
MPC		0.59
ClinPred		0.010	T
GERP RS		4.3
gMVP		0.28
Mutation Taster		=77/23	polymorphism

Splicing

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

Other links and lift over

dbSNP: rs61745397; hg19: chr3-124117557;