chr1-202892579-C-A

Position:

• chr1-202892579-C-A

Variant summary

Our verdict is Uncertain significance. Variant got 1 ACMG points: 2P and 1B. PM2 BP4

The NM_021633.4(KLHL12):​c.1661G>T​(p.Gly554Val) 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. 13/21 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: 4.90

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 1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.35940936).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
KLHL12	NM_021633.4	c.1661G>T	p.Gly554Val	missense_variant	12/12	ENST00000367261.8	NP_067646.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
KLHL12	ENST00000367261.8	c.1661G>T	p.Gly554Val	missense_variant	12/12	1	NM_021633.4	ENSP00000356230	P1
KLHL12	ENST00000367259.1	c.*58G>T		3_prime_UTR_variant	6/6	2		ENSP00000356228

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

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 29, 2021

The c.1661G>T (p.G554V) alteration is located in exon 12 (coding exon 11) of the KLHL12 gene. This alteration results from a G to T substitution at nucleotide position 1661, causing the glycine (G) at amino acid position 554 to be replaced by a valine (V). 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	0.16
BayesDel_addAF	Uncertain	0.019	T
BayesDel_noAF	Benign	-0.21
CADD	Benign	23
DANN	Benign	0.96
DEOGEN2	Benign	0.36	T
Eigen	Benign	-0.077
Eigen_PC	Benign	0.12
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Uncertain	0.92	D
M_CAP	Benign	0.022	T
MetaRNN	Benign	0.36	T
MetaSVM	Benign	-0.89	T
MutationAssessor	Benign	0.79	N
MutationTaster	Benign	1.0	D;D;D
PrimateAI	Uncertain	0.68	T
PROVEAN	Benign	-2.2	N
REVEL	Benign	0.20
Sift	Benign	0.065	T
Sift4G	Benign	0.51	T
Polyphen		0.021	B
Vest4		0.52
MutPred		0.56		Gain of loop (P = 0.2045);
MVP		0.85
MPC		0.91
ClinPred		0.69	D
GERP RS		5.0
Varity_R		0.60
gMVP		0.44

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

No publications associated with this variant yet.

Other links and lift over

hg19: chr1-202861707;