X-9786562-C-T

Variant summary

Our verdict is Likely benign. Variant got -3 ACMG points: 0P and 3B. BP4_ModerateBS2_Supporting

The NM_001649.4(SHROOM2):​c.17C>T​(p.Pro6Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000937 in 853,901 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 3 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 0.000045 ( 0 hom., 2 hem., cov: 23)
Exomes 𝑓: 0.0000040 ( 0 hom. 1 hem. )

Consequence

SHROOM2
NM_001649.4 missense

Scores

3
1
13

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 0.324
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]

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Likely_benign. Variant got -3 ACMG points.

BP4
Computational evidence support a benign effect (MetaRNN=0.09159398).
BS2
High Hemizygotes in GnomAd4 at 2 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 rank MANE Protein UniProt
SHROOM2NM_001649.4 linkc.17C>T p.Pro6Leu missense_variant Exon 1 of 10 ENST00000380913.8 NP_001640.1 Q13796
SHROOM2XM_005274500.5 linkc.17C>T p.Pro6Leu missense_variant Exon 1 of 10 XP_005274557.2

Ensembl

Gene Transcript HGVSc HGVSp Effect Exon rank TSL MANE Protein Appris UniProt
SHROOM2ENST00000380913.8 linkc.17C>T p.Pro6Leu missense_variant Exon 1 of 10 1 NM_001649.4 ENSP00000370299.3 Q13796

Frequencies

GnomAD3 genomes
AF:
0.0000362
AC:
4
AN:
110356
Hom.:
0
Cov.:
23
AF XY:
0.0000590
AC XY:
2
AN XY:
33914
show subpopulations
Gnomad AFR
AF:
0.0000648
Gnomad AMI
AF:
0.00
Gnomad AMR
AF:
0.00
Gnomad ASJ
AF:
0.00
Gnomad EAS
AF:
0.000578
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
AF:
0.00000403
AC:
3
AN:
743508
Hom.:
0
Cov.:
28
AF XY:
0.00000443
AC XY:
1
AN XY:
225692
show subpopulations
Gnomad4 AFR exome
AF:
0.0000662
Gnomad4 AMR exome
AF:
0.00
Gnomad4 ASJ exome
AF:
0.00
Gnomad4 EAS exome
AF:
0.00
Gnomad4 SAS exome
AF:
0.00
Gnomad4 FIN exome
AF:
0.00
Gnomad4 NFE exome
AF:
0.00
Gnomad4 OTH exome
AF:
0.0000722
GnomAD4 genome
AF:
0.0000453
AC:
5
AN:
110393
Hom.:
0
Cov.:
23
AF XY:
0.0000589
AC XY:
2
AN XY:
33961
show subpopulations
Gnomad4 AFR
AF:
0.0000969
Gnomad4 AMR
AF:
0.00
Gnomad4 ASJ
AF:
0.00
Gnomad4 EAS
AF:
0.000581
Gnomad4 SAS
AF:
0.00
Gnomad4 FIN
AF:
0.00
Gnomad4 NFE
AF:
0.00
Gnomad4 OTH
AF:
0.00
Alfa
AF:
0.000214
Hom.:
1
Bravo
AF:
0.0000453

ClinVar

Significance: Uncertain significance
Submissions summary: Uncertain:1
Revision: criteria provided, single submitter
LINK: link

Submissions by phenotype

not specified Uncertain:1
Sep 19, 2022
Ambry Genetics
Significance: Uncertain significance
Review Status: criteria provided, single submitter
Collection Method: clinical testing

The c.17C>T (p.P6L) alteration is located in exon 1 (coding exon 1) of the SHROOM2 gene. This alteration results from a C to T substitution at nucleotide position 17, causing the proline (P) at amino acid position 6 to be replaced by a leucine (L). 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
0.32
BayesDel_addAF
Benign
-0.35
T
BayesDel_noAF
Benign
-0.73
CADD
Benign
21
DANN
Uncertain
1.0
DEOGEN2
Benign
0.036
T
FATHMM_MKL
Benign
0.17
N
LIST_S2
Benign
0.62
T
M_CAP
Pathogenic
0.37
D
MetaRNN
Benign
0.092
T
MetaSVM
Benign
-0.99
T
MutationAssessor
Benign
0.0
N
PrimateAI
Pathogenic
0.89
D
PROVEAN
Benign
-1.2
N
REVEL
Benign
0.011
Sift
Pathogenic
0.0
D
Sift4G
Benign
0.25
T
Polyphen
0.012
B
Vest4
0.17
MutPred
0.21
Loss of glycosylation at P6 (P = 0.0422);
MVP
0.60
MPC
0.30
ClinPred
0.42
T
GERP RS
1.4
Varity_R
0.21
gMVP
0.22

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: rs933648472; hg19: chrX-9754602; API