Genetic Variant DIAPH2:p.Arg1091Cys (chrX-97599282-C-T) – ACMG Classification: Likely_benign (-5 pts)

Variant summary

Our verdict is Likely benign. Variant got -5 ACMG points: 0P and 5B. BP4BS2

The NM_006729.5(DIAPH2):c.3271C>T(p.Arg1091Cys) variant causes a missense change. The variant allele was found at a frequency of 0.0000176 in 1,193,202 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 8 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.0000089 ( 0 hom., 0 hem., cov: 23)

Exomes 𝑓: 0.000019 ( 0 hom. 8 hem. )

Consequence

DIAPH2
NM_006729.5 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 5.28

Variant links:

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]

DIAPH2 links:

DIAPH2-AS1 (HGNC:16972): (DIAPH2 antisense RNA 1)

DIAPH2-AS1 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Likely_benign. Variant got -5 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.3342104).

BS2

High Hemizygotes in GnomAdExome4 at 8 XL gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
DIAPH2	NM_006729.5 link	c.3271C>T	p.Arg1091Cys	missense_variant	Exon 27 of 27	ENST00000324765.13	NP_006720.1	O60879-1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
DIAPH2	ENST00000324765.13 link	c.3271C>T	p.Arg1091Cys	missense_variant	Exon 27 of 27	1	NM_006729.5	ENSP00000321348.8		O60879-1
DIAPH2-AS1	ENST00000445414.1 link	n.349+3529G>A		intron_variant	Intron 2 of 2	2

Frequencies

GnomAD3 genomes

AF:

0.00000891

AC:

AN:

112222

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

34394

show subpopulations

Gnomad AFR

AF:

0.00

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:

0.0000188

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.0000467

AC:

AN:

171181

Hom.:

AF XY:

0.0000351

AC XY:

AN XY:

56949

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.000533

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000132

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000185

AC:

AN:

1080980

Hom.:

Cov.:

AF XY:

0.0000229

AC XY:

AN XY:

348924

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.000203

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.0000157

Gnomad4 OTH exome

AF:

0.0000221

GnomAD4 genome

AF:

0.00000891

AC:

AN:

112222

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

34394

show subpopulations

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000188

Gnomad4 OTH

AF:

0.00

Bravo

AF:

0.0000340

ESP6500AA

AF:

0.00

AC:

ESP6500EA

AF:

0.000149

AC:

ExAC

AF:

0.0000412

AC:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Jan 30, 2024

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.3271C>T (p.R1091C) alteration is located in exon 27 (coding exon 27) of the DIAPH2 gene. This alteration results from a C to T substitution at nucleotide position 3271, causing the arginine (R) at amino acid position 1091 to be replaced by a cysteine (C). 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

Pathogenic

0.93

BayesDel_addAF

Pathogenic

0.19

BayesDel_noAF

Uncertain

0.030

CADD

Benign

DANN

Pathogenic

1.0

DEOGEN2

Uncertain

0.44

.;T

FATHMM_MKL

Uncertain

0.84

LIST_S2

Uncertain

0.93

D;D

M_CAP

Pathogenic

0.33

MetaRNN

Benign

0.33

T;T

MetaSVM

Uncertain

0.43

MutationAssessor

Benign

0.34

.;N

PrimateAI

Uncertain

0.72

PROVEAN

Benign

0.31

N;N

REVEL

Uncertain

0.58

Sift

Benign

0.039

D;D

Sift4G

Uncertain

0.043

D;D

Polyphen

1.0

.;D

Vest4

0.47

MVP

0.80

MPC

1.2

ClinPred

0.29

GERP RS

5.2

Varity_R

0.17

gMVP

0.44

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.020

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over