1-202911134-C-T

Position:

• chr1-202911134-C-T

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_021633.4(KLHL12):​c.637G>A​(p.Glu213Lys) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 14/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: KLHL12 NM_021633.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 4.10

Genes affected

KLHL12 (HGNC:19360): (kelch like family member 12) This gene encodes a member of the KLHL (Kelch-like) family of proteins. This protein has been identified as an autoantigen in the autoimmune disease Sjogren's syndrome and as a potential biomarker in primary biliary cirrhosis. This protein may act as a substrate adaptor of the Cullin-3 ubiquitin ligase complex to promote substrate-specific ubiquitylation. Ubiquitylation by this complex has been shown to regulate the Wnt signaling pathway as well as COPII vesicle coat size. A pseudogene has been identified on chromosome 22. Alternative splicing results in multiple transcript variants. [provided by RefSeq, Dec 2014]

ACMG classification

Verdict is Uncertain_significance. Variant got 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.14664143).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
KLHL12	NM_021633.4	c.637G>A	p.Glu213Lys	missense_variant	5/12	ENST00000367261.8	NP_067646.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
KLHL12	ENST00000367261.8	c.637G>A	p.Glu213Lys	missense_variant	5/12	1	NM_021633.4	ENSP00000356230	P1
KLHL12	ENST00000367258.1	c.751G>A	p.Glu251Lys	missense_variant	5/6	5		ENSP00000356227

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

Bravo AF: 0.00000378

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Oct 17, 2023

The c.637G>A (p.E213K) alteration is located in exon 5 (coding exon 4) of the KLHL12 gene. This alteration results from a G to A substitution at nucleotide position 637, causing the glutamic acid (E) at amino acid position 213 to be replaced by a lysine (K). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.087
BayesDel_addAF	Benign	-0.082	T
BayesDel_noAF	Benign	-0.36
CADD	Benign	22
DANN	Uncertain	1.0
DEOGEN2	Benign	0.24	T;T
Eigen	Benign	-0.26
Eigen_PC	Benign	0.015
FATHMM_MKL	Uncertain	0.93	D
LIST_S2	Benign	0.85	T;T
M_CAP	Benign	0.0065	T
MetaRNN	Benign	0.15	T;T
MetaSVM	Benign	-0.92	T
MutationAssessor	Benign	-0.47	N;.
MutationTaster	Benign	0.82	D;D
PrimateAI	Benign	0.41	T
PROVEAN	Benign	-1.3	N;N
REVEL	Benign	0.059
Sift	Benign	0.24	T;T
Sift4G	Benign	0.75	T;.
Polyphen		0.0	B;.
Vest4		0.19
MutPred		0.44		Gain of MoRF binding (P = 0.0134);.;
MVP		0.77
MPC		0.79
ClinPred		0.72	D
GERP RS		5.6
Varity_R		0.15
gMVP		0.20

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

Publications

LitVar

Other links and lift over

dbSNP: rs1660341169; hg19: chr1-202880262;