Genetic Variant FAM86B2:p.Lys273Gln (chr8-12427732-T-G) – ACMG Classification: Benign (-10 pts)

Variant summary

Our verdict is Benign. Variant got -10 ACMG points: 0P and 10B. BP4_StrongBP6_ModerateBS2

The NM_001137610.3(FAM86B2):c.817A>C(p.Lys273Gln) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000946 in 998,024 control chromosomes in the GnomAD database, including 250 homozygotes. 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 Likely benign (★).

Frequency

Genomes: 𝑓 0.00046 ( 7 hom., cov: 13)

Exomes 𝑓: 0.00095 ( 250 hom. )

Failed GnomAD Quality Control

Consequence

FAM86B2
NM_001137610.3 missense

Scores

Clinical Significance

Likely benign criteria provided, single submitter B:1

Conservation

PhyloP100: 0.705

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 Benign. Variant got -10 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.009946704).

BP6

Variant 8-12427732-T-G is Benign according to our data. Variant chr8-12427732-T-G is described in ClinVar as [Likely_benign]. Clinvar id is 2359804.Status of the report is criteria_provided_single_submitter, 1 stars.

BS2

High Homozygotes in GnomAdExome4 at 250 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
FAM86B2	NM_001137610.3 link	c.817A>C	p.Lys273Gln	missense_variant	Exon 7 of 8	ENST00000262365.9	NP_001131082.1	P0C5J1
FAM86B2	NR_148876.2 link	n.506A>C		non_coding_transcript_exon_variant	Exon 5 of 6
FAM86B2	NR_148877.2 link	n.425A>C		non_coding_transcript_exon_variant	Exon 4 of 5
FAM86B2	NR_148878.2 link	n.706A>C		non_coding_transcript_exon_variant	Exon 6 of 7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
FAM86B2	ENST00000262365.9 link	c.817A>C	p.Lys273Gln	missense_variant	Exon 7 of 8	5	NM_001137610.3	ENSP00000262365.4		P0C5J1

Frequencies

GnomAD3 genomes

AF:

0.000464

AC:

AN:

90466

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000154

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000241

Gnomad ASJ

AF:

0.00104

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00260

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000661

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.000501

AC:

AN:

161700

Hom.:

AF XY:

0.000558

AC XY:

AN XY:

89648

show subpopulations

Gnomad AFR exome

AF:

0.0000987

Gnomad AMR exome

AF:

0.000249

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.000425

Gnomad SAS exome

AF:

0.00157

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.000421

Gnomad OTH exome

AF:

0.000501

GnomAD4 exome

AF:

0.000946

AC:

944

AN:

998024

Hom.:

250

Cov.:

AF XY:

0.000976

AC XY:

486

AN XY:

498110

show subpopulations

Gnomad4 AFR exome

AF:

0.000116

Gnomad4 AMR exome

AF:

0.000503

Gnomad4 ASJ exome

AF:

0.0000626

Gnomad4 EAS exome

AF:

0.000593

Gnomad4 SAS exome

AF:

0.00238

Gnomad4 FIN exome

AF:

0.0000335

Gnomad4 NFE exome

AF:

0.000957

Gnomad4 OTH exome

AF:

0.000692

GnomAD4 genome

Data not reliable, filtered out with message: AS_VQSR

AF:

0.000464

AC:

AN:

90544

Hom.:

Cov.:

AF XY:

0.000598

AC XY:

AN XY:

43462

show subpopulations

Gnomad4 AFR

AF:

0.000153

Gnomad4 AMR

AF:

0.000240

Gnomad4 ASJ

AF:

0.00104

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00261

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.000661

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.00118

Hom.:

ExAC

AF:

0.000555

AC:

ClinVar

Significance: Likely benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Benign:1

Mar 11, 2022

Ambry Genetics

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.064

BayesDel_addAF

Benign

-0.38

BayesDel_noAF

Benign

-0.78

CADD

Benign

0.86

DANN

Benign

0.21

DEOGEN2

Benign

0.0018

T;T;.

Eigen

Benign

-1.4

Eigen_PC

Benign

-1.5

FATHMM_MKL

Benign

0.0025

LIST_S2

Benign

0.10

T;T;T

M_CAP

Benign

0.0012

MetaRNN

Benign

0.0099

T;T;T

MetaSVM

Benign

-1.0

MutationAssessor

Benign

-0.48

N;.;.

PrimateAI

Uncertain

0.55

PROVEAN

Benign

0.34

N;.;N

REVEL

Benign

0.013

Sift

Benign

1.0

T;.;T

Sift4G

Benign

0.64

T;T;T

Polyphen

0.0

B;.;.

Vest4

0.040

MutPred

0.39

Gain of sheet (P = 0.0149);.;.;

MVP

0.068

MPC

1.8

ClinPred

0.00017

GERP RS

0.55

Varity_R

0.049

gMVP

0.28

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.

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