20-18389752-G-A

Variant summary

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

The NM_001367614.1(DZANK1):c.2042C>T(p.Ala681Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000137 in 1,461,680 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 16/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.000014 (0 hom.)
• Consequence: DZANK1 NM_001367614.1 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.885

Genes affected

DZANK1 (HGNC:15858): (double zinc ribbon and ankyrin repeat domains 1) This gene contains two ankyrin repeat-encoding regions. Ankyrin repeats are tandemly repeated modules of about 33 amino acids described as L-shaped structures consisting of a beta-hairpin and two alpha-helices. Ankyrin repeats occur in a large number of functionally diverse proteins, mainly from eukaryotes, and are known to function as protein-protein interaction domains. [provided by RefSeq, Dec 2018]

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=0.15546483).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
DZANK1	NM_001367614.1	c.2042C>T	p.Ala681Val	missense_variant	19/21	ENST00000699568.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
DZANK1	ENST00000699568.1	c.2042C>T	p.Ala681Val	missense_variant	19/21		NM_001367614.1	P2

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 0.0000137 AC: 20 AN: 1461680 Hom.: 0 Cov.: 30 AF XY: 0.0000151 AC XY: 11 AN XY: 727120

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000116

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000162

Gnomad4 OTH exome AF: 0.0000166

GnomAD4 genome Cov.: 33

Bravo AF: 0.00000756

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

Jul 27, 2022

The c.1967C>T (p.A656V) alteration is located in exon 19 (coding exon 18) of the DZANK1 gene. This alteration results from a C to T substitution at nucleotide position 1967, causing the alanine (A) at amino acid position 656 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	0.075
BayesDel_addAF	Benign	-0.091	T
BayesDel_noAF	Benign	-0.37
Cadd	Benign	9.2
Dann	Benign	0.65
DEOGEN2	Benign	0.0028	T;T;T;.
Eigen	Benign	-0.81
Eigen_PC	Benign	-0.83
FATHMM_MKL	Benign	0.24	N
LIST_S2	Benign	0.81	T;T;.;T
M_CAP	Benign	0.010	T
MetaRNN	Benign	0.16	T;T;T;T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	-0.14	N;.;N;.
MutationTaster	Benign	1.0	N;N;N;N
PrimateAI	Benign	0.34	T
PROVEAN	Benign	-1.3	N;.;.;N
REVEL	Benign	0.14
Sift	Benign	0.62	T;.;.;T
Sift4G	Benign	1.0	T;T;T;T
Polyphen		0.021	B;.;B;.
Vest4		0.28
MutPred		0.59		Gain of relative solvent accessibility (P = 0.1571);.;Gain of relative solvent accessibility (P = 0.1571);.;
MVP		0.23
MPC		0.044
ClinPred		0.17	T
GERP RS		0.63
Varity_R		0.024
gMVP		0.22

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: rs1313127515; hg19: chr20-18370396;