Genetic Variant SHROOM2:p.Lys55Arg (chrX-9786709-A-G) – 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.164A>G(p.Lys55Arg) variant causes a missense, splice region change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000633 in 884,142 control chromosomes in the GnomAD database, including 1 homozygotes. There are 20 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. 2/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.00011 ( 0 hom., 6 hem., cov: 24)

Exomes 𝑓: 0.000057 ( 1 hom. 14 hem. )

Consequence

SHROOM2
NM_001649.4 missense, splice_region

Scores

Splicing: ADA: 0.7276

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 3.54

Publications

0 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=0.07906625).

BS2

High Hemizygotes in GnomAd4 at 6 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.164A>G	p.Lys55Arg	missense splice_region	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.164A>G	p.Lys55Arg	missense splice_region	Exon 1 of 10	ENSP00000370299.3	Q13796
	ENSG00000310579	ENST00000850985.1		c.164A>G	p.Lys55Arg	missense splice_region	Exon 1 of 10	ENSP00000521067.1

Frequencies

GnomAD3 genomes

AF:

0.000108

AC:

AN:

111305

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:

0.00348

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:

0.0000569

AC:

AN:

772793

Hom.:

Cov.:

AF XY:

0.0000596

AC XY:

AN XY:

234923

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

15952

American (AMR)

AF:

0.00

AC:

AN:

4684

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

8274

East Asian (EAS)

AF:

0.00266

AC:

AN:

15436

South Asian (SAS)

AF:

0.00

AC:

AN:

13711

European-Finnish (FIN)

AF:

0.00

AC:

AN:

13878

Middle Eastern (MID)

AF:

0.00

AC:

AN:

1772

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

669363

Other (OTH)

AF:

0.000101

AC:

AN:

29723

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.495

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:

0.000108

AC:

AN:

111349

Hom.:

Cov.:

AF XY:

0.000176

AC XY:

AN XY:

34165

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

31007

American (AMR)

AF:

0.00

AC:

AN:

10756

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

2631

East Asian (EAS)

AF:

0.00349

AC:

AN:

3437

South Asian (SAS)

AF:

0.00

AC:

AN:

2798

European-Finnish (FIN)

AF:

0.00

AC:

AN:

5785

Middle Eastern (MID)

AF:

0.00

AC:

AN:

215

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

52538

Other (OTH)

AF:

0.00

AC:

AN:

1513

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.508

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome 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

Alfa

AF:

0.00

Hom.:

Bravo

AF:

0.000280

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

Benign

0.24

BayesDel_addAF

Benign

-0.60

BayesDel_noAF

Benign

-0.63

CADD

Uncertain

(source)

DANN

Uncertain

0.99

DEOGEN2

Benign

0.10

FATHMM_MKL

Uncertain

0.83

LIST_S2

Benign

0.80

M_CAP

Uncertain

0.12

MetaRNN

Benign

0.079

MetaSVM

Benign

-1.1

MutationAssessor

Benign

1.3

PhyloP100

3.5

PrimateAI

Pathogenic

0.82

PROVEAN

Benign

-1.4

REVEL

Benign

0.032

Sift

Benign

0.22

Sift4G

Benign

0.071

Polyphen

0.069

Vest4

0.20

MutPred

0.47

Loss of ubiquitination at K55 (P = 0.0071)

MVP

0.31

MPC

0.064

ClinPred

0.42

GERP RS

2.9

PromoterAI

-0.078

Neutral

(source)

Varity_R

0.14

gMVP

0.18

Mutation Taster

=89/11

polymorphism

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

dbscSNV1_ADA

Benign

0.73

dbscSNV1_RF

Pathogenic

0.73

SpliceAI score (max)

0.010

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