X-96738710-G-C

Variant summary

Our verdict is Likely benign. Variant got -6 ACMG points: 0P and 6B. BP4_Moderate BS2

The NM_006729.5(DIAPH2):c.290G>C(p.Arg97Pro) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000821 in 1,095,696 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 5 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 22)
  • Exomes 𝑓: 0.0000082 (0 hom. 5 hem.)
• Consequence: DIAPH2 NM_006729.5 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 7.59

Genes affected

DIAPH2 (HGNC:2877): (diaphanous related formin 2) The product of this gene belongs to the diaphanous subfamily of the formin homology family of proteins. This gene may play a role in the development and normal function of the ovaries. Defects in this gene have been linked to premature ovarian failure 2. Alternatively spliced transcript variants encoding different isoforms have been identified. [provided by RefSeq, Jul 2008]

ACMG classification

Verdict is Likely_benign. Variant got -6 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.15930983).
• BS2: High Hemizygotes in GnomAdExome at 2 XL gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
DIAPH2	NM_006729.5	c.290G>C	p.Arg97Pro	missense_variant	3/27	ENST00000324765.13
DIAPH2	NM_007309.4	c.290G>C	p.Arg97Pro	missense_variant	3/27

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
DIAPH2	ENST00000324765.13	c.290G>C	p.Arg97Pro	missense_variant	3/27	1	NM_006729.5	A2
DIAPH2	ENST00000373049.8	c.290G>C	p.Arg97Pro	missense_variant	3/27	1		P3

Frequencies

GnomAD3 genomes Cov.: 22

GnomAD3 exomes AF: 0.0000221 AC: 4 AN: 180597 Hom.: 0 AF XY: 0.0000306 AC XY: 2 AN XY: 65295

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.000220

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000821 AC: 9 AN: 1095696 Hom.: 0 Cov.: 29 AF XY: 0.0000138 AC XY: 5 AN XY: 361256

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: 0.000131

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00

Gnomad4 OTH exome AF: 0.0000435

GnomAD4 genome Cov.: 22

ExAC AF: 0.0000247 AC: 3

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.290G>C (p.R97P) alteration is located in exon 3 (coding exon 3) of the DIAPH2 gene. This alteration results from a G to C substitution at nucleotide position 290, causing the arginine (R) at amino acid position 97 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	0.24
BayesDel_addAF	Uncertain	0.015	T
BayesDel_noAF	Uncertain	0.070
Cadd	Benign	21
Dann	Uncertain	0.99
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Benign	0.81	T;T;T;T;T
M_CAP	Uncertain	0.10	D
MetaRNN	Benign	0.16	T;T;T;T;T
MetaSVM	Uncertain	0.077	D
MutationTaster	Benign	1.0	D;D;D;D;D
PrimateAI	Uncertain	0.61	T
PROVEAN	Benign	-1.3	N;N;N;N;.
REVEL	Uncertain	0.56
Sift	Benign	0.30	T;T;T;T;.
Sift4G	Benign	0.28	T;T;T;T;T
Polyphen		1.0, 0.13	.;.;D;B;.
Vest4		0.36
MutPred		0.33		Loss of helix (P = 0.0558);Loss of helix (P = 0.0558);Loss of helix (P = 0.0558);Loss of helix (P = 0.0558);Loss of helix (P = 0.0558);
MVP		0.90
MPC		0.47
ClinPred		0.34	T
GERP RS		4.6
Varity_R		0.43
gMVP		0.83

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: rs764249440; hg19: chrX-95993709;