3-98799814-A-G

Variant summary

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

The NM_080927.4(DCBLD2):c.1886T>C(p.Ile629Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000409 in 1,612,724 control chromosomes in the GnomAD database, including 1 homozygotes. 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: 𝑓 0.00024 (0 hom., cov: 32)
  • Exomes 𝑓: 0.000020 (1 hom.)
• Consequence: DCBLD2 NM_080927.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 2.74

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=0.042834044).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
DCBLD2	NM_080927.4	c.1886T>C	p.Ile629Thr	missense_variant	16/16	ENST00000326840.11
DCBLD2	XM_011512419.3	c.1658T>C	p.Ile553Thr	missense_variant	15/15
DCBLD2	XM_024453348.2	c.1568T>C	p.Ile523Thr	missense_variant	16/16

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
DCBLD2	ENST00000326840.11	c.1886T>C	p.Ile629Thr	missense_variant	16/16	1	NM_080927.4	P1
DCBLD2	ENST00000326857.9	c.1928T>C	p.Ile643Thr	missense_variant	16/16	1
ST3GAL6	ENST00000491912.1	n.254-1608A>G		intron_variant, non_coding_transcript_variant		3
DCBLD2	ENST00000496736.1			downstream_gene_variant		3

Frequencies

GnomAD3 genomes AF: 0.000243 AC: 37 AN: 152202 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00236

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: 0.0000147

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.000110 AC: 27 AN: 245164 Hom.: 1 AF XY: 0.000105 AC XY: 14 AN XY: 133192

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.000787

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: 0.0000199 AC: 29 AN: 1460522 Hom.: 1 Cov.: 32 AF XY: 0.0000193 AC XY: 14 AN XY: 726416

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.000605

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: 9.00e-7

Gnomad4 OTH exome AF: 0.0000166

GnomAD4 genome AF: 0.000243 AC: 37 AN: 152202 Hom.: 0 Cov.: 32 AF XY: 0.000350 AC XY: 26 AN XY: 74356

Gnomad4 AFR AF: 0.00

Gnomad4 AMR AF: 0.00236

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000147

Gnomad4 OTH AF: 0.00

Bravo AF: 0.000106

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

Sep 17, 2021

The c.1886T>C (p.I629T) alteration is located in exon 16 (coding exon 16) of the DCBLD2 gene. This alteration results from a T to C substitution at nucleotide position 1886, causing the isoleucine (I) at amino acid position 629 to be replaced by a threonine (T). 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	0.12
BayesDel_addAF	Benign	-0.42	T
BayesDel_noAF	Benign	-0.47
Cadd	Benign	17
Dann	Benign	0.85
DEOGEN2	Benign	0.00060	T;.
Eigen	Benign	-0.17
Eigen_PC	Benign	-0.019
FATHMM_MKL	Benign	0.75	D
LIST_S2	Benign	0.81	T;T
M_CAP	Benign	0.0053	T
MetaRNN	Benign	0.043	T;T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	0.63	N;.
MutationTaster	Benign	0.77	D;D
PrimateAI	Uncertain	0.66	T
PROVEAN	Benign	-0.020	N;N
REVEL	Benign	0.087
Sift	Benign	0.71	T;T
Sift4G	Benign	0.42	T;T
Polyphen		0.36	B;P
Vest4		0.10
MutPred		0.47		Gain of glycosylation at I629 (P = 0.0106);.;
MVP		0.36
MPC		0.14
ClinPred		0.083	T
GERP RS		4.5
Varity_R		0.038
gMVP		0.31

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: rs1399302463; hg19: chr3-98518658;