1-43971398-A-C

Position:

• chr1-43971398-A-C

Variant summary

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

The NM_001384.5(DPH2):​c.496A>C​(p.Thr166Pro) 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. 14/21 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)
• Consequence: DPH2 NM_001384.5 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.253

Genes affected

DPH2 (HGNC:3004): (diphthamide biosynthesis 2) This gene is one of two human genes similar to the yeast gene dph2. The yeast gene was identified by its ability to complement a diphthamide mutant strain, and thus probably functions in diphthamide biosynthesis. Diphthamide is a post-translationally modified histidine residue present in elongation factor 2 (EF2) that is the target of diphtheria toxin ADP-ribosylation. Multiple transcript variants encoding different isoforms have been found for this gene. [provided by RefSeq, Jan 2016]

DPH2 (HGNC:):

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=0.201101).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
DPH2	NM_001384.5	c.496A>C	p.Thr166Pro	missense_variant	4/6	ENST00000255108.8	NP_001375.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
DPH2	ENST00000255108.8	c.496A>C	p.Thr166Pro	missense_variant	4/6	1	NM_001384.5	ENSP00000255108.3

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 33

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

Nov 07, 2023

The c.496A>C (p.T166P) alteration is located in exon 4 (coding exon 4) of the DPH2 gene. This alteration results from a A to C substitution at nucleotide position 496, causing the threonine (T) at amino acid position 166 to be replaced by a proline (P). 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	0.13
BayesDel_addAF	Benign	-0.12	T
BayesDel_noAF	Benign	-0.41
CADD	Benign	15
DANN	Benign	0.91
DEOGEN2	Benign	0.082	T
Eigen	Benign	-0.26
Eigen_PC	Benign	-0.27
FATHMM_MKL	Benign	0.093	N
LIST_S2	Benign	0.59	T
M_CAP	Benign	0.013	T
MetaRNN	Benign	0.20	T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	1.6	L
PrimateAI	Uncertain	0.65	T
PROVEAN	Benign	-1.6	N
REVEL	Benign	0.098
Sift	Benign	0.13	T
Sift4G	Benign	0.20	T
Polyphen		0.52	P
Vest4		0.45
MutPred		0.45		Gain of disorder (P = 0.0115);
MVP		0.49
MPC		0.34
ClinPred		0.20	T
GERP RS		2.3
Varity_R		0.18
gMVP		0.79

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.050		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: rs1571783805; hg19: chr1-44437070;