chr19-11174532-G-A

Variant names:

• chr19-11174532-G-A
• rs606231303
• NM_001136191.3:c.2009C>T

Variant summary

Our verdict is Uncertain significance. The variant received 5 ACMG points: 5P and 0B. PM2 PP3_Moderate PP5

The NM_001136191.3(KANK2):​c.2009C>T​(p.Ala670Val) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Pathogenic (no stars).

• Frequency: Genomes: not found (cov: 33)
• Consequence: KANK2 NM_001136191.3 missense
• Clinical Significance: Pathogenic no assertion criteria provided P:1
• Conservation: PhyloP100: 9.59
• Publications: 2 publications found

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]

KANK2 Gene-Disease associations (from GenCC):

• wooly hair-palmoplantar keratoderma syndrome

  Inheritance: AR, Unknown Classification: SUPPORTIVE, LIMITED Submitted by: G2P, Orphanet, Labcorp Genetics (formerly Invitae)
• nephrotic syndrome 16

  Inheritance: Unknown Classification: LIMITED Submitted by: Labcorp Genetics (formerly Invitae)

ACMG classification

Our verdict: Uncertain_significance. The variant received 5 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.929
• PP5: Variant 19-11174532-G-A is Pathogenic according to our data. Variant chr19-11174532-G-A is described in ClinVar as Pathogenic. ClinVar VariationId is 158088.Status of the report is no_assertion_criteria_provided, 0 stars.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001136191.3. 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
	KANK2	NM_001136191.3	MANE Select	c.2009C>T	p.Ala670Val	missense	Exon 9 of 13	NP_001129663.1
	KANK2	NM_001379548.1		c.2033C>T	p.Ala678Val	missense	Exon 9 of 13	NP_001366477.1
	KANK2	NM_001379549.1		c.2033C>T	p.Ala678Val	missense	Exon 9 of 13	NP_001366478.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	KANK2	ENST00000586659.6	TSL:1 MANE Select	c.2009C>T	p.Ala670Val	missense	Exon 9 of 13	ENSP00000465650.1
	KANK2	ENST00000589359.5	TSL:5	c.2033C>T	p.Ala678Val	missense	Exon 9 of 13	ENSP00000468002.1
	KANK2	ENST00000589894.1	TSL:5	c.2009C>T	p.Ala670Val	missense	Exon 7 of 10	ENSP00000467029.1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 33

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:1

Revision: no assertion criteria provided

Submissions by phenotype

Wooly hair-palmoplantar keratoderma syndrome Pathogenic:1

Jun 01, 2014

OMIM

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: literature only

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.65
BayesDel_addAF	Uncertain	0.11	D
BayesDel_noAF	Uncertain	-0.070
CADD	Uncertain	24
DANN	Pathogenic	1.0
DEOGEN2	Benign	0.15	T
Eigen	Uncertain	0.54
Eigen_PC	Uncertain	0.52
FATHMM_MKL	Pathogenic	1.0	D
LIST_S2	Pathogenic	0.99	D
M_CAP	Pathogenic	0.43	D
MetaRNN	Pathogenic	0.93	D
MetaSVM	Uncertain	-0.16	T
MutationAssessor	Benign	2.0	M
PhyloP100		9.6
PrimateAI	Uncertain	0.70	T
Sift4G	Uncertain	0.0040	D
Polyphen		1.0	D
Vest4		0.81
MutPred		0.77		Loss of disorder (P = 0.0682)
MVP		0.68
ClinPred		0.98	D
GERP RS		5.0
Varity_R		0.82
gMVP		0.73
Mutation Taster		=1/99	disease causing (ClinVar)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.0		Details are displayed if max score is > 0.2

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

Other links and lift over

dbSNP: rs606231303; hg19: chr19-11285208;