20-18384509-C-T

Variant names:

• chr20-18384509-C-T
• rs2048360681
• NM_001367614.1:c.2224G>A

Variant summary

Our verdict is Likely pathogenic. The variant received 6 ACMG points: 6P and 0B. PM2 PP3_Strong

The NM_001367614.1(DZANK1):​c.2224G>A​(p.Ala742Thr) variant causes a missense change. The variant allele was found at a frequency of 0.000000685 in 1,459,330 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. A742S) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 6.9e-7 (0 hom.)
• Consequence: DZANK1 NM_001367614.1 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 5.99
• Publications: 0 publications found

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

Our verdict: Likely_pathogenic. The variant received 6 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.958

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001367614.1. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	DZANK1	NM_001367614.1	MANE Select	c.2224G>A	p.Ala742Thr	missense	Exon 21 of 21	NP_001354543.1	A0A8V8TNE5
	DZANK1	NM_001367617.1		c.2224G>A	p.Ala742Thr	missense	Exon 21 of 21	NP_001354546.1	A0A8V8TNE5
	DZANK1	NM_001367618.1		c.2224G>A	p.Ala742Thr	missense	Exon 21 of 21	NP_001354547.1	A0A8V8TNE5

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	DZANK1	ENST00000699568.1	MANE Select	c.2224G>A	p.Ala742Thr	missense	Exon 21 of 21	ENSP00000514442.1	A0A8V8TNE5
	DZANK1	ENST00000699590.1		c.2182G>A	p.Ala728Thr	missense	Exon 21 of 21	ENSP00000514461.1	A0A8V8TPU7
	DZANK1	ENST00000699525.1		c.2167G>A	p.Ala723Thr	missense	Exon 21 of 21	ENSP00000514418.1	A0A8V8TNH6

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 6.85e-7 AC: 1 AN: 1459330 Hom.: 0 Cov.: 31 AF XY: 0.00000138 AC XY: 1 AN XY: 725624

African (AFR) AF: 0.00 AC: 0 AN: 33440

American (AMR) AF: 0.00 AC: 0 AN: 44342

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26010

East Asian (EAS) AF: 0.00 AC: 0 AN: 39662

South Asian (SAS) AF: 0.00 AC: 0 AN: 85536

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53304

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5762

European-Non Finnish (NFE) AF: 9.00e-7 AC: 1 AN: 1110962

Other (OTH) AF: 0.00 AC: 0 AN: 60312

GnomAD4 genome Cov.: 32

Alfa AF: 0.0000312 Hom.: 0

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.40
BayesDel_addAF	Pathogenic	0.36	D
BayesDel_noAF	Pathogenic	0.28
CADD	Uncertain	26
DANN	Pathogenic	1.0
DEOGEN2	Benign	0.20	T
Eigen	Uncertain	0.54
Eigen_PC	Uncertain	0.54
FATHMM_MKL	Uncertain	0.96	D
LIST_S2	Uncertain	0.90	D
M_CAP	Uncertain	0.21	D
MetaRNN	Pathogenic	0.96	D
MetaSVM	Uncertain	0.37	D
MutationAssessor	Uncertain	2.4	M
PhyloP100		6.0
PrimateAI	Benign	0.45	T
PROVEAN	Uncertain	-3.8	D
REVEL	Pathogenic	0.81
Sift	Pathogenic	0.0	D
Sift4G	Pathogenic	0.0	D
Polyphen		1.0	D
Vest4		0.90
MutPred		0.79		Loss of stability (P = 0.1246)
MVP		0.67
MPC		0.29
ClinPred		0.99	D
GERP RS		5.6
Varity_R		0.73
gMVP		0.62
Mutation Taster		=58/42	polymorphism

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

Other links and lift over

dbSNP: rs2048360681; hg19: chr20-18365153;