Genetic Variant FAM86B2:p.Pro241Ser (chr8-12428654-G-A) – ACMG Classification: Uncertain_significance (1 pts)

Variant summary

Our verdict is Uncertain significance. Variant got 1 ACMG points: 2P and 1B. PM2BP4

The NM_001137610.3(FAM86B2):c.721C>T(p.Pro241Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000206 in 145,646 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 13/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.000021 ( 0 hom., cov: 23)

Exomes 𝑓: 0.0000015 ( 0 hom. )

Failed GnomAD Quality Control

Consequence

FAM86B2
NM_001137610.3 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 1.15

Variant links:

Genes affected

FAM86B2 (HGNC:32222): (family with sequence similarity 86 member B2) Predicted to enable methyltransferase activity. Predicted to be involved in methylation. Part of protein-containing complex. [provided by Alliance of Genome Resources, Apr 2022]

FAM86B2 links:

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ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 1 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.32704878).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
FAM86B2	NM_001137610.3 link	c.721C>T	p.Pro241Ser	missense_variant	Exon 6 of 8	ENST00000262365.9	NP_001131082.1	P0C5J1
FAM86B2	NR_148876.2 link	n.431+327C>T		intron_variant	Intron 4 of 5
FAM86B2	NR_148877.2 link	n.350+327C>T		intron_variant	Intron 3 of 4
FAM86B2	NR_148878.2 link	n.631+327C>T		intron_variant	Intron 5 of 6

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
FAM86B2	ENST00000262365.9 link	c.721C>T	p.Pro241Ser	missense_variant	Exon 6 of 8	5	NM_001137610.3	ENSP00000262365.4		P0C5J1

Frequencies

GnomAD3 genomes

AF:

0.0000206

AC:

AN:

145646

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000508

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:

0.0000151

Gnomad OTH

AF:

0.00

GnomAD4 exome

Data not reliable, filtered out with message: AS_VQSR

AF:

0.00000151

AC:

AN:

1327052

Hom.:

Cov.:

AF XY:

0.00000153

AC XY:

AN XY:

654940

show subpopulations

Gnomad4 AFR exome

AF:

0.00

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:

0.00000192

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

AF:

0.0000206

AC:

AN:

145646

Hom.:

Cov.:

AF XY:

0.0000141

AC XY:

AN XY:

70726

show subpopulations

Gnomad4 AFR

AF:

0.0000508

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000151

Gnomad4 OTH

AF:

0.00

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Jul 17, 2024

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.721C>T (p.P241S) alteration is located in exon 6 (coding exon 6) of the FAM86B2 gene. This alteration results from a C to T substitution at nucleotide position 721, causing the proline (P) at amino acid position 241 to be replaced by a serine (S). 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

0.19

BayesDel_addAF

Benign

-0.25

BayesDel_noAF

Benign

-0.60

CADD

Benign

DANN

Benign

0.96

DEOGEN2

Benign

0.033

T;.

Eigen

Benign

-0.35

Eigen_PC

Benign

-0.44

FATHMM_MKL

Benign

0.52

LIST_S2

Benign

0.81

T;T

M_CAP

Benign

0.0046

MetaRNN

Benign

0.33

T;T

MetaSVM

Benign

-1.1

MutationAssessor

Benign

1.9

L;.

PrimateAI

Uncertain

0.61

PROVEAN

Benign

-2.1

N;N

REVEL

Benign

0.074

Sift

Benign

0.33

T;T

Sift4G

Benign

0.17

T;T

Polyphen

0.57

P;.

Vest4

0.21

MutPred

0.69

Loss of stability (P = 0.133);.;

MVP

0.082

MPC

3.0

ClinPred

0.18

GERP RS

1.2

Varity_R

0.084

gMVP

0.46

Splicing

Name

Calibrated prediction

Score

Prediction

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

LitVar

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

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over