19-49374915-A-G

Position:

• chr19-49374915-A-G

Variant summary

Our verdict is Likely benign. Variant got -4 ACMG points: 2P and 6B. PM2 BP4_Strong BP6_Moderate

The NM_014419.4(DKKL1):​c.616A>G​(p.Lys206Glu) 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. 15/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★).

• Frequency: Genomes: not found (cov: 31)
• Consequence: DKKL1 NM_014419.4 missense
• Clinical Significance: Likely benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 1.35

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]

ENSG00000268686 (HGNC:):

ACMG classification

Verdict is Likely_benign. Variant got -4 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.022195727).
• BP6: Variant 19-49374915-A-G is Benign according to our data. Variant chr19-49374915-A-G is described in ClinVar as [Likely_benign]. Clinvar id is 2548759.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
DKKL1	NM_014419.4	c.616A>G	p.Lys206Glu	missense_variant	5/5	ENST00000221498.7	NP_055234.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
DKKL1	ENST00000221498.7	c.616A>G	p.Lys206Glu	missense_variant	5/5	1	NM_014419.4	ENSP00000221498.1

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD4 exome Cov.: 34

GnomAD4 genome Cov.: 31

ClinVar

Significance: Likely benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Ambry Genetics

May 18, 2023

This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.066
BayesDel_addAF	Benign	-0.28	T
BayesDel_noAF	Benign	-0.64
CADD	Benign	6.0
DANN	Benign	0.21
DEOGEN2	Benign	0.0040	T;T;T;T
Eigen	Benign	-1.0
Eigen_PC	Benign	-0.87
FATHMM_MKL	Benign	0.0095	N
LIST_S2	Benign	0.55	T;T;T;T
M_CAP	Benign	0.0040	T
MetaRNN	Benign	0.022	T;T;T;T
MetaSVM	Benign	-0.93	T
MutationAssessor	Benign	-1.4	.;.;N;.
PrimateAI	Benign	0.30	T
PROVEAN	Benign	0.46	.;.;N;.
REVEL	Benign	0.033
Sift	Benign	1.0	.;.;T;.
Sift4G	Benign	1.0	T;T;T;T
Polyphen		0.0	.;.;B;.
Vest4		0.065
MutPred		0.12		.;.;Loss of ubiquitination at K206 (P = 0.0056);.;
MVP		0.088
MPC		0.20
ClinPred		0.033	T
GERP RS		3.0
Varity_R		0.061
gMVP		0.026

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: rs953466250; hg19: chr19-49878172;