X-9894539-G-A

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PP5_ModerateBP4BS2_Supporting

The NM_001649.4(SHROOM2):​c.631G>A​(p.Gly211Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00327 in 1,209,486 control chromosomes in the GnomAD database, including 12 homozygotes. There are 1,276 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. 13/19 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★).

Frequency

Genomes: 𝑓 0.0023 ( 1 hom., 87 hem., cov: 24)
Exomes 𝑓: 0.0034 ( 11 hom. 1189 hem. )

Consequence

SHROOM2
NM_001649.4 missense

Scores

3
13

Clinical Significance

Likely pathogenic criteria provided, single submitter P:1

Conservation

PhyloP100: 3.45
Variant links:
Genes affected
SHROOM2 (HGNC:630): (shroom family member 2) This gene represents the human homolog of Xenopus laevis apical protein (APX) gene, which is implicated in amiloride-sensitive sodium channel activity. It is expressed in endothelial cells and facilitates the formation of a contractile network within endothelial cells. Depletion of this gene results in an increase in endothelial sprouting, migration, and angiogenesis. This gene is highly expressed in the retina, and is a strong candidate for ocular albinism type 1 syndrome. Alternatively spliced transcript variants have been found for this gene. [provided by RefSeq, Mar 2016]

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ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 0 ACMG points.

PP5
Variant X-9894539-G-A is Pathogenic according to our data. Variant chrX-9894539-G-A is described in ClinVar as [Likely_pathogenic]. Clinvar id is 1174005.Status of the report is criteria_provided_single_submitter, 1 stars.
BP4
Computational evidence support a benign effect (MetaRNN=0.006932944). . Strength limited to SUPPORTING due to the PP5.
BS2
High Hemizygotes in GnomAd4 at 87 geneVariant has number of hemizygotes lower than other variant known as pathogenic in the gene, so the strength is limited to Supporting.

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE Protein UniProt
SHROOM2NM_001649.4 linkc.631G>A p.Gly211Ser missense_variant 4/10 ENST00000380913.8 NP_001640.1 Q13796
SHROOM2XM_005274500.5 linkc.631G>A p.Gly211Ser missense_variant 4/10 XP_005274557.2

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Protein Appris UniProt
SHROOM2ENST00000380913.8 linkc.631G>A p.Gly211Ser missense_variant 4/101 NM_001649.4 ENSP00000370299.3 Q13796

Frequencies

GnomAD3 genomes
AF:
0.00233
AC:
259
AN:
111291
Hom.:
1
Cov.:
24
AF XY:
0.00260
AC XY:
87
AN XY:
33479
show subpopulations
Gnomad AFR
AF:
0.000262
Gnomad AMI
AF:
0.00
Gnomad AMR
AF:
0.00265
Gnomad ASJ
AF:
0.00
Gnomad EAS
AF:
0.00
Gnomad SAS
AF:
0.00
Gnomad FIN
AF:
0.0139
Gnomad MID
AF:
0.00
Gnomad NFE
AF:
0.00253
Gnomad OTH
AF:
0.00338
GnomAD3 exomes
AF:
0.00346
AC:
632
AN:
182798
Hom.:
1
AF XY:
0.00343
AC XY:
231
AN XY:
67380
show subpopulations
Gnomad AFR exome
AF:
0.000457
Gnomad AMR exome
AF:
0.000766
Gnomad ASJ exome
AF:
0.00
Gnomad EAS exome
AF:
0.00
Gnomad SAS exome
AF:
0.000105
Gnomad FIN exome
AF:
0.0156
Gnomad NFE exome
AF:
0.00405
Gnomad OTH exome
AF:
0.00553
GnomAD4 exome
AF:
0.00336
AC:
3694
AN:
1098146
Hom.:
11
Cov.:
32
AF XY:
0.00327
AC XY:
1189
AN XY:
363514
show subpopulations
Gnomad4 AFR exome
AF:
0.000341
Gnomad4 AMR exome
AF:
0.000710
Gnomad4 ASJ exome
AF:
0.000103
Gnomad4 EAS exome
AF:
0.0000331
Gnomad4 SAS exome
AF:
0.0000554
Gnomad4 FIN exome
AF:
0.0167
Gnomad4 NFE exome
AF:
0.00336
Gnomad4 OTH exome
AF:
0.00312
GnomAD4 genome
AF:
0.00231
AC:
257
AN:
111340
Hom.:
1
Cov.:
24
AF XY:
0.00259
AC XY:
87
AN XY:
33538
show subpopulations
Gnomad4 AFR
AF:
0.000261
Gnomad4 AMR
AF:
0.00255
Gnomad4 ASJ
AF:
0.00
Gnomad4 EAS
AF:
0.00
Gnomad4 SAS
AF:
0.00
Gnomad4 FIN
AF:
0.0139
Gnomad4 NFE
AF:
0.00251
Gnomad4 OTH
AF:
0.00334
Alfa
AF:
0.00262
Hom.:
99
Bravo
AF:
0.00180
TwinsUK
AF:
0.00162
AC:
6
ALSPAC
AF:
0.00346
AC:
10
ESP6500AA
AF:
0.000522
AC:
2
ESP6500EA
AF:
0.00312
AC:
21
ExAC
AF:
0.00355
AC:
431
EpiCase
AF:
0.00245
EpiControl
AF:
0.00296

ClinVar

Significance: Likely pathogenic
Submissions summary: Pathogenic:1
Revision: criteria provided, single submitter
LINK: link

Submissions by phenotype

Meniere disease Pathogenic:1
Likely pathogenic, criteria provided, single submittercase-controlOtology & Neurotology- Genomics of vestibular disorders (CTS-495), Jose Antonio López Escámez, Centro Pfizer - Universidad de Granada - Junta de Andalucía de Genómica e Investigación Oncológica (GENYO)Jun 21, 2021Digenic inheritance along with NM_000260.4:c.3G>A(MYO7A) -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Benign
0.099
BayesDel_addAF
Benign
-0.41
T
BayesDel_noAF
Benign
-0.36
CADD
Benign
13
DANN
Uncertain
1.0
DEOGEN2
Benign
0.055
T
FATHMM_MKL
Uncertain
0.79
D
LIST_S2
Uncertain
0.86
D
MetaRNN
Benign
0.0069
T
MetaSVM
Benign
-0.99
T
MutationAssessor
Benign
0.38
N
PrimateAI
Benign
0.43
T
PROVEAN
Benign
-1.9
N
REVEL
Benign
0.22
Sift
Benign
0.42
T
Sift4G
Benign
0.95
T
Polyphen
0.97
D
Vest4
0.061
MVP
0.68
MPC
0.42
ClinPred
0.022
T
GERP RS
3.3
Varity_R
0.12
gMVP
0.27

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

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

Other links and lift over

dbSNP: rs138558321; hg19: chrX-9862579; API