Genetic Variant SHROOM2:p.Arg25Ser (chrX-9786618-C-A) – ACMG Classification: Likely_benign (-3 pts)

Variant summary

Our verdict is Likely benign. The variant received -3 ACMG points: 0P and 3B. BP4_ModerateBS2_Supporting

The NM_001649.4(SHROOM2):c.73C>A(p.Arg25Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000227 in 879,464 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 7 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 0.000027 ( 0 hom., 0 hem., cov: 24)

Exomes 𝑓: 0.000022 ( 0 hom. 7 hem. )

Consequence

SHROOM2
NM_001649.4 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: -0.136

Publications

1 publications found

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]

SHROOM2 links:

ENSG00000310579 (HGNC:):

ENSG00000310579 links:

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ACMG classification

Classification was made for transcript

Our verdict: Likely_benign. The variant received -3 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.167689).

BS2

High Hemizygotes in GnomAdExome4 at 7 geneVariant has number of hemizygotes lower than other variant known as pathogenic in the gene, so the strength is limited to Supporting.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001649.4. 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
	SHROOM2	NM_001649.4	MANE Select	c.73C>A	p.Arg25Ser	missense	Exon 1 of 10	NP_001640.1	Q13796

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SHROOM2	ENST00000380913.8	TSL:1 MANE Select	c.73C>A	p.Arg25Ser	missense	Exon 1 of 10	ENSP00000370299.3	Q13796
	ENSG00000310579	ENST00000850985.1		c.73C>A	p.Arg25Ser	missense	Exon 1 of 10	ENSP00000521067.1

Frequencies

GnomAD3 genomes

AF:

0.0000271

AC:

AN:

110785

Hom.:

Cov.:

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:

0.000868

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:

0.0000221

AC:

AN:

768679

Hom.:

Cov.:

AF XY:

0.0000299

AC XY:

AN XY:

234313

show subpopulations

African (AFR)

AF:

0.0000632

AC:

AN:

15827

American (AMR)

AF:

0.00

AC:

AN:

4587

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

8125

East Asian (EAS)

AF:

0.000814

AC:

AN:

14749

South Asian (SAS)

AF:

0.00

AC:

AN:

13718

European-Finnish (FIN)

AF:

0.00

AC:

AN:

13613

Middle Eastern (MID)

AF:

0.00

AC:

AN:

1738

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

666894

Other (OTH)

AF:

0.000136

AC:

AN:

29428

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.530

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.0000271

AC:

AN:

110785

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

34025

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

30925

American (AMR)

AF:

0.00

AC:

AN:

10662

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

2629

East Asian (EAS)

AF:

0.000868

AC:

AN:

3455

South Asian (SAS)

AF:

0.00

AC:

AN:

2817

European-Finnish (FIN)

AF:

0.00

AC:

AN:

5477

Middle Eastern (MID)

AF:

0.00

AC:

AN:

235

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

52407

Other (OTH)

AF:

0.00

AC:

AN:

1501

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.542

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.00

Hom.:

Bravo

AF:

0.0000302

ClinVar

ClinVar submissions

Significance:Uncertain significance

Revision:criteria provided, single submitter

View on ClinVar

Pathogenic

VUS

Benign

Condition

not specified (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Uncertain

0.50

BayesDel_addAF

Benign

-0.28

BayesDel_noAF

Benign

-0.63

CADD

Benign

(source)

DANN

Uncertain

0.98

DEOGEN2

Benign

0.060

FATHMM_MKL

Benign

0.16

LIST_S2

Benign

0.53

M_CAP

Pathogenic

0.42

MetaRNN

Benign

0.17

MetaSVM

Benign

-1.0

MutationAssessor

Benign

-0.28

PhyloP100

-0.14

PrimateAI

Pathogenic

0.93

PROVEAN

Benign

-2.3

REVEL

Benign

0.12

Sift

Uncertain

0.0060

Sift4G

Uncertain

0.016

Polyphen

0.35

Vest4

0.42

MutPred

0.41

Gain of phosphorylation at R25 (P = 0.0343)

MVP

0.70

MPC

0.32

ClinPred

0.42

GERP RS

1.7

PromoterAI

-0.0082

Neutral

(source)

Varity_R

0.33

gMVP

0.26

Mutation Taster

=89/11

polymorphism

(source)

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over