Genetic Variant NM_001387468.1:c.622T>C (chrX-134781858-A-G) – ACMG Classification: Likely_benign (-6 pts)

Variant summary

Our verdict is Likely benign. The variant received -6 ACMG points: 0P and 6B. BP4_ModerateBS2

The NM_001387468.1(PABIR2):c.622T>C(p.Ser208Pro) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000233 in 1,202,334 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 10 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. 14/21 in silico tools predict 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: 0.000021 ( 0 hom. 8 hem. )

Consequence

PABIR2
NM_001387468.1 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 2.72

Publications

0 publications found

Variant links:

Genes affected

PABIR2 (HGNC:30490): (PABIR family member 2) Predicted to enable protein serine/threonine phosphatase inhibitor activity. Predicted to be involved in negative regulation of catalytic activity. Predicted to be part of collagen trimer. [provided by Alliance of Genome Resources, Apr 2022]

PABIR2 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Likely_benign. The variant received -6 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.15656337).

BS2

High Hemizygotes in GnomAd4 at 2 gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PABIR2	NM_001387468.1 link	c.622T>C	p.Ser208Pro	missense_variant	Exon 9 of 10	ENST00000343004.10	NP_001374397.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
PABIR2	ENST00000343004.10 link	c.622T>C	p.Ser208Pro	missense_variant	Exon 9 of 10	1	NM_001387468.1	ENSP00000339207.6		G1UD79

Frequencies

GnomAD3 genomes

AF:

0.0000449

AC:

AN:

111265

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:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000943

Gnomad OTH

AF:

0.00

GnomAD2 exomes

AF:

0.00000558

AC:

AN:

179159

AF XY:

0.0000157

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000124

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000211

AC:

AN:

1091018

Hom.:

Cov.:

AF XY:

0.0000224

AC XY:

AN XY:

357692

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

26312

American (AMR)

AF:

0.00

AC:

AN:

34911

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

19205

East Asian (EAS)

AF:

0.00

AC:

AN:

30113

South Asian (SAS)

AF:

0.00

AC:

AN:

52784

European-Finnish (FIN)

AF:

0.00

AC:

AN:

39797

Middle Eastern (MID)

AF:

0.00

AC:

AN:

4109

European-Non Finnish (NFE)

AF:

0.0000251

AC:

AN:

837993

Other (OTH)

AF:

0.0000437

AC:

AN:

45794

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.455

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

AF:

0.0000449

AC:

AN:

111316

Hom.:

Cov.:

AF XY:

0.0000597

AC XY:

AN XY:

33524

show subpopulations

⚠️ The allele balance in gnomAD version 4 Genomes is significantly skewed from the expected value of 0.5.

African (AFR)

AF:

0.00

AC:

AN:

30687

American (AMR)

AF:

0.00

AC:

AN:

10365

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

2643

East Asian (EAS)

AF:

0.00

AC:

AN:

3582

South Asian (SAS)

AF:

0.00

AC:

AN:

2663

European-Finnish (FIN)

AF:

0.00

AC:

AN:

5918

Middle Eastern (MID)

AF:

0.00

AC:

AN:

217

European-Non Finnish (NFE)

AF:

0.0000943

AC:

AN:

53040

Other (OTH)

AF:

0.00

AC:

AN:

1521

⚠️ The allele balance in gnomAD version 4 Genomes is significantly skewed from the expected value of 0.5. (p-value = 0.022510), which strongly suggests a high chance of mosaicism in these individuals.

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.375

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Alfa

AF:

0.00

Hom.:

Bravo

AF:

0.00000756

TwinsUK

AF:

0.000270

AC:

ALSPAC

AF:

0.00

AC:

ExAC

AF:

0.0000165

AC:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

May 10, 2022

Ambry Genetics

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

The c.619T>C (p.S207P) alteration is located in exon 9 (coding exon 9) of the FAM122B gene. This alteration results from a T to C substitution at nucleotide position 619, causing the serine (S) at amino acid position 207 to be replaced by a proline (P). 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

0.075

BayesDel_addAF

Benign

-0.072

BayesDel_noAF

Benign

-0.34

CADD

Benign

8.2

(source)

DANN

Uncertain

0.99

DEOGEN2

Uncertain

0.44

T;T;.;.;.;T

FATHMM_MKL

Uncertain

0.91

LIST_S2

Benign

0.75

T;T;T;T;T;.

M_CAP

Benign

0.025

MetaRNN

Benign

0.16

T;T;T;T;T;T

MetaSVM

Benign

-0.88

MutationAssessor

Benign

1.9

L;.;.;.;.;.

PhyloP100

2.7

PrimateAI

Benign

0.44

PROVEAN

Uncertain

-2.8

D;.;D;D;.;.

REVEL

Benign

0.18

Sift

Uncertain

0.0020

D;.;D;D;.;.

Sift4G

Benign

0.11

T;T;T;T;T;T

Polyphen

0.013

B;.;.;B;B;.

Vest4

0.34

MutPred

0.21

Gain of catalytic residue at S188 (P = 0.0061);.;.;.;.;.;

MVP

0.54

MPC

0.79

ClinPred

0.35

GERP RS

3.3

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.0

Varity_R

0.37

gMVP

0.45

Mutation Taster

=44/56

disease causing

(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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NM_001387468.1:c.622T>C

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over