3-98799515-G-T

Variant summary

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

The NM_080927.4(DCBLD2):c.2185C>A(p.Gln729Lys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000694 in 1,613,978 control chromosomes in the GnomAD database, with no homozygous occurrence. 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 Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.00033 (0 hom., cov: 32)
  • Exomes 𝑓: 0.000042 (0 hom.)
• Consequence: DCBLD2 NM_080927.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 3.56

Genes affected

DCBLD2 (HGNC:24627): (discoidin, CUB and LCCL domain containing 2) Involved in negative regulation of cell growth and wound healing. Located in cell surface. Is integral component of plasma membrane. [provided by Alliance of Genome Resources, Apr 2022]

ST3GAL6 (HGNC:18080): (ST3 beta-galactoside alpha-2,3-sialyltransferase 6) The protein encoded by this gene is a member of the sialyltransferase family. Members of this family are enzymes that transfer sialic acid from the activated cytidine 5'-monophospho-N-acetylneuraminic acid to terminal positions on sialylated glycolipids (gangliosides) or to the N- or O-linked sugar chains of glycoproteins. This protein has high specificity for neolactotetraosylceramide and neolactohexaosylceramide as glycolipid substrates and may contribute to the formation of selectin ligands and sialyl Lewis X, a carbohydrate important for cell-to-cell recognition and a blood group antigen. [provided by RefSeq, Apr 2016]

ACMG classification

Verdict is Likely_benign. Variant got -2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.015273392).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
DCBLD2	NM_080927.4	c.2185C>A	p.Gln729Lys	missense_variant	16/16	ENST00000326840.11
DCBLD2	XM_011512419.3	c.1957C>A	p.Gln653Lys	missense_variant	15/15
DCBLD2	XM_024453348.2	c.1867C>A	p.Gln623Lys	missense_variant	16/16

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
DCBLD2	ENST00000326840.11	c.2185C>A	p.Gln729Lys	missense_variant	16/16	1	NM_080927.4	P1
DCBLD2	ENST00000326857.9	c.2227C>A	p.Gln743Lys	missense_variant	16/16	1
ST3GAL6	ENST00000491912.1	n.254-1907G>T		intron_variant, non_coding_transcript_variant		3

Frequencies

GnomAD3 genomes AF: 0.000329 AC: 50 AN: 152158 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.00121

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.0000723 AC: 18 AN: 249046 Hom.: 0 AF XY: 0.0000518 AC XY: 7 AN XY: 135098

Gnomad AFR exome AF: 0.00103

Gnomad AMR exome AF: 0.0000579

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000424 AC: 62 AN: 1461702 Hom.: 0 Cov.: 32 AF XY: 0.0000344 AC XY: 25 AN XY: 727132

Gnomad4 AFR exome AF: 0.00155

Gnomad4 AMR exome AF: 0.0000447

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00

Gnomad4 OTH exome AF: 0.000133

GnomAD4 genome AF: 0.000328 AC: 50 AN: 152276 Hom.: 0 Cov.: 32 AF XY: 0.000322 AC XY: 24 AN XY: 74466

Gnomad4 AFR AF: 0.00120

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.00

Gnomad4 OTH AF: 0.00

Alfa AF: 0.000151 Hom.: 0

Bravo AF: 0.000457

ESP6500AA AF: 0.00153 AC: 6

ESP6500EA AF: 0.00 AC: 0

ExAC AF: 0.0000744 AC: 9

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

Dec 19, 2022

The c.2185C>A (p.Q729K) alteration is located in exon 16 (coding exon 16) of the DCBLD2 gene. This alteration results from a C to A substitution at nucleotide position 2185, causing the glutamine (Q) at amino acid position 729 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	0.074
BayesDel_addAF	Benign	-0.56	T
BayesDel_noAF	Benign	-0.63
Cadd	Benign	19
Dann	Benign	0.95
DEOGEN2	Benign	0.0044	T;.
Eigen	Benign	-0.081
Eigen_PC	Benign	0.089
FATHMM_MKL	Uncertain	0.77	D
LIST_S2	Benign	0.78	T;T
M_CAP	Benign	0.0042	T
MetaRNN	Benign	0.015	T;T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	1.6	L;.
MutationTaster	Benign	0.66	N;N
PrimateAI	Benign	0.21	T
PROVEAN	Benign	-0.82	N;N
REVEL	Benign	0.065
Sift	Benign	0.35	T;T
Sift4G	Benign	0.29	T;T
Polyphen		0.0090	B;B
Vest4		0.076
MVP		0.23
MPC		0.13
ClinPred		0.046	T
GERP RS		5.1
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.13
gMVP		0.26

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.030		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: rs200981832; hg19: chr3-98518359;