19-49365856-G-C

Position:

• chr19-49365856-G-C

Variant summary

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

The NM_014419.4(DKKL1):​c.388G>C​(p.Ala130Pro) variant causes a missense change involving the alteration of a non-conserved nucleotide. 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. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency: Genomes: not found (cov: 32)
• Consequence: DKKL1 NM_014419.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 1.62

Genes affected

DKKL1 (HGNC:16528): (dickkopf like acrosomal protein 1) The dickkopf protein family interacts with the Wnt signaling pathway and its members are characterized by two conserved cysteine-rich domains. This gene encodes a secreted protein that has low sequence similarity to the dickkopf-3 protein. Multiple alternatively spliced transcript variants encoding distinct isoforms have been found for this gene. [provided by RefSeq, Oct 2010]

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=0.08650994).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
DKKL1	NM_014419.4	c.388G>C	p.Ala130Pro	missense_variant	4/5	ENST00000221498.7	NP_055234.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
DKKL1	ENST00000221498.7	c.388G>C	p.Ala130Pro	missense_variant	4/5	1	NM_014419.4	ENSP00000221498.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 33

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

Aug 10, 2024

The c.388G>C (p.A130P) alteration is located in exon 4 (coding exon 4) of the DKKL1 gene. This alteration results from a G to C substitution at nucleotide position 388, causing the alanine (A) at amino acid position 130 to be replaced by a proline (P). 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	0.19
BayesDel_addAF	Benign	-0.23	T
BayesDel_noAF	Benign	-0.57
CADD	Benign	16
DANN	Uncertain	0.98
DEOGEN2	Benign	0.026	T;T;T
Eigen	Benign	-0.34
Eigen_PC	Benign	-0.50
FATHMM_MKL	Benign	0.073	N
LIST_S2	Benign	0.71	T;T;T
M_CAP	Benign	0.0060	T
MetaRNN	Benign	0.087	T;T;T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	1.0	.;L;.
PrimateAI	Benign	0.26	T
PROVEAN	Benign	-1.2	.;N;.
REVEL	Benign	0.047
Sift	Benign	0.084	.;T;.
Sift4G	Benign	0.095	T;T;T
Polyphen		0.96	.;D;.
Vest4		0.20
MutPred		0.21		.;Gain of disorder (P = 0.0412);.;
MVP		0.030
MPC		0.43
ClinPred		0.32	T
GERP RS		1.9
Varity_R		0.12
gMVP		0.17

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: chr19-49869113;