19-11166602-T-C

Position:

• chr19-11166602-T-C

Variant summary

Our verdict is Benign. Variant got -16 ACMG points: 0P and 16B. BP4_Strong BP6_Very_Strong BS2

The NM_001136191.3(KANK2):​c.2512A>G​(p.Met838Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00251 in 1,614,094 control chromosomes in the GnomAD database, including 5 homozygotes. In-silico tool predicts a benign outcome for this variant. 12/19 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0019 (0 hom., cov: 32)
  • Exomes 𝑓: 0.0026 (5 hom.)
• Consequence: KANK2 NM_001136191.3 missense
• Clinical Significance: Likely benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: 2.81

Genes affected

KANK2 (HGNC:29300): (KN motif and ankyrin repeat domains 2) This gene encodes a member of the KN motif and ankyrin repeat domains (KANK) family of proteins, which play a role in cytoskeletal formation by regulating actin polymerization. The encoded protein functions in the sequestration of steroid receptor coactivators and possibly other proteins. Mutations in this gene are associated with impaired kidney podocyte function and nephrotic syndrome, and keratoderma and woolly hair. [provided by RefSeq, Jul 2016]

ACMG classification

Verdict is Benign. Variant got -16 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.010030568).
• BP6: Variant 19-11166602-T-C is Benign according to our data. Variant chr19-11166602-T-C is described in ClinVar as [Likely_benign]. Clinvar id is 1554484.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS2: High Homozygotes in GnomAdExome4 at 5 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
KANK2	NM_001136191.3	c.2512A>G	p.Met838Val	missense_variant	13/13	ENST00000586659.6	NP_001129663.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
KANK2	ENST00000586659.6	c.2512A>G	p.Met838Val	missense_variant	13/13	1	NM_001136191.3	ENSP00000465650	P1
KANK2	ENST00000589359.5	c.2536A>G	p.Met846Val	missense_variant	13/13	5		ENSP00000468002
KANK2	ENST00000588787.5	c.622A>G	p.Met208Val	missense_variant	5/5	5		ENSP00000464896
KANK2	ENST00000587317.1	n.379A>G		non_coding_transcript_exon_variant	4/4	2

Frequencies

GnomAD3 genomes AF: 0.00190 AC: 289 AN: 152190 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.000869

Gnomad AMI AF: 0.00110

Gnomad AMR AF: 0.00229

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.000385

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.0000941

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00312

Gnomad OTH AF: 0.000957

GnomAD3 exomes AF: 0.00180 AC: 449 AN: 249312 Hom.: 0 AF XY: 0.00182 AC XY: 245 AN XY: 134942

Gnomad AFR exome AF: 0.000431

Gnomad AMR exome AF: 0.00278

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.000326

Gnomad SAS exome AF: 0.000196

Gnomad FIN exome AF: 0.000185

Gnomad NFE exome AF: 0.00280

Gnomad OTH exome AF: 0.00277

GnomAD4 exome AF: 0.00257 AC: 3758 AN: 1461786 Hom.: 5 Cov.: 32 AF XY: 0.00244 AC XY: 1776 AN XY: 727192

Gnomad4 AFR exome AF: 0.000478

Gnomad4 AMR exome AF: 0.00219

Gnomad4 ASJ exome AF: 0.0000765

Gnomad4 EAS exome AF: 0.000252

Gnomad4 SAS exome AF: 0.000151

Gnomad4 FIN exome AF: 0.000281

Gnomad4 NFE exome AF: 0.00311

Gnomad4 OTH exome AF: 0.00230

GnomAD4 genome AF: 0.00190 AC: 289 AN: 152308 Hom.: 0 Cov.: 32 AF XY: 0.00185 AC XY: 138 AN XY: 74478

Gnomad4 AFR AF: 0.000866

Gnomad4 AMR AF: 0.00229

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.000386

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.0000941

Gnomad4 NFE AF: 0.00312

Gnomad4 OTH AF: 0.000947

Alfa AF: 0.00254 Hom.: 3

Bravo AF: 0.00209

TwinsUK AF: 0.00189 AC: 7

ALSPAC AF: 0.00389 AC: 15

ESP6500AA AF: 0.00136 AC: 6

ESP6500EA AF: 0.00349 AC: 30

ExAC AF: 0.00195 AC: 237

Asia WGS AF: 0.000577 AC: 2 AN: 3478

EpiCase AF: 0.00316

EpiControl AF: 0.00403

ClinVar

Significance: Likely benign

Submissions summary: Benign:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Likely benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 07, 2024	- -
Likely benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -

KANK2-related disorder Benign:1

Likely benign, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

Feb 14, 2022

This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.098
BayesDel_addAF	Benign	-0.40	T
BayesDel_noAF	Benign	-0.35
CADD	Benign	18
DANN	Benign	0.79
DEOGEN2	Benign	0.0032	T;.
Eigen	Benign	-0.43
Eigen_PC	Benign	-0.34
FATHMM_MKL	Uncertain	0.78	D
LIST_S2	Benign	0.71	T;T
M_CAP	Benign	0.023	T
MetaRNN	Benign	0.010	T;T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	-0.34	N;.
MutationTaster	Benign	0.81	N;N;N;N
PrimateAI	Uncertain	0.52	T
Sift4G	Benign	0.62	T;T
Polyphen		0.23	B;B
Vest4		0.45
MVP		0.56
ClinPred		0.019	T
GERP RS		3.1
Varity_R		0.13
gMVP		0.19

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.030		Details are displayed if max score is > 0.2

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

Publications

LitVar

Other links and lift over

dbSNP: rs117057052; hg19: chr19-11277278; COSMIC: COSV100763514; COSMIC: COSV100763514;