1-43971438-G-C

Variant names:

• chr1-43971438-G-C
• rs1270622734
• NM_001384.5:c.536G>C

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_001384.5(DPH2):​c.536G>C​(p.Ser179Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000657 in 152,214 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 0.0000066 (0 hom., cov: 33)
• Consequence: DPH2 NM_001384.5 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 2.01
• Publications: 0 publications found

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]

ENSG00000285649 (HGNC:):

ACMG classification

Our verdict: Uncertain_significance. The variant received 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.13211417).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001384.5. 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
	DPH2	NM_001384.5	MANE Select	c.536G>C	p.Ser179Thr	missense	Exon 4 of 6	NP_001375.2
	DPH2	NM_001319165.2		c.308G>C	p.Ser103Thr	missense	Exon 4 of 6	NP_001306094.1	B3KRB8
	DPH2	NM_001319168.2		c.308G>C	p.Ser103Thr	missense	Exon 4 of 6	NP_001306097.1	B3KRB8

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	DPH2	ENST00000255108.8	TSL:1 MANE Select	c.536G>C	p.Ser179Thr	missense	Exon 4 of 6	ENSP00000255108.3	Q9BQC3-1
	DPH2	ENST00000922599.1		c.554G>C	p.Ser185Thr	missense	Exon 4 of 6	ENSP00000592658.1
	DPH2	ENST00000955917.1		c.536G>C	p.Ser179Thr	missense	Exon 4 of 6	ENSP00000625976.1

Frequencies

GnomAD3 genomes AF: 0.00000657 AC: 1 AN: 152214 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.0000241

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

GnomAD4 exome Cov.: 31

GnomAD4 genome AF: 0.00000657 AC: 1 AN: 152214 Hom.: 0 Cov.: 33 AF XY: 0.00 AC XY: 0 AN XY: 74364

African (AFR) AF: 0.0000241 AC: 1 AN: 41458

American (AMR) AF: 0.00 AC: 0 AN: 15284

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5196

South Asian (SAS) AF: 0.00 AC: 0 AN: 4832

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10616

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 316

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 68036

Other (OTH) AF: 0.00 AC: 0 AN: 2092

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.00000756

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.084
BayesDel_addAF	Benign	-0.15	T
BayesDel_noAF	Benign	-0.46
CADD	Benign	22
DANN	Benign	0.91
DEOGEN2	Benign	0.032	T
Eigen	Benign	-0.27
Eigen_PC	Benign	-0.085
FATHMM_MKL	Uncertain	0.87	D
LIST_S2	Benign	0.64	T
M_CAP	Benign	0.0047	T
MetaRNN	Benign	0.13	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	0.65	N
PhyloP100		2.0
PrimateAI	Uncertain	0.60	T
PROVEAN	Benign	-0.15	N
REVEL	Benign	0.082
Sift	Benign	0.55	T
Sift4G	Benign	0.49	T
Polyphen		0.080	B
Vest4		0.22
MutPred		0.55		Gain of glycosylation at S179 (P = 0.0714)
MVP		0.48
MPC		0.23
ClinPred		0.14	T
GERP RS		3.7
PromoterAI		0.0099	Neutral
Varity_R		0.053
gMVP		0.37
Mutation Taster		=94/6	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.080		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: rs1270622734; hg19: chr1-44437110;