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

Variant summary

Our verdict is Benign. The variant received -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. 15/22 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

Publications

1 publications found

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:

FAM66A (HGNC:30444): (family with sequence similarity 66 member A)

FAM66A links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -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 VariationId is 2359804.Status of the report is criteria_provided_single_submitter, 1 stars.

BS2

High Homozygotes in GnomAdExome4 at 250 AR gene

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001137610.3. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
FAM86B2	NM_001137610.3	MANE Select	c.817A>C	p.Lys273Gln	missense	Exon 7 of 8	NP_001131082.1	P0C5J1
FAM86B2	NR_148876.2		n.506A>C		non_coding_transcript_exon	Exon 5 of 6
FAM86B2	NR_148877.2		n.425A>C		non_coding_transcript_exon	Exon 4 of 5

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
FAM86B2	ENST00000262365.9	TSL:5 MANE Select	c.817A>C	p.Lys273Gln	missense	Exon 7 of 8	ENSP00000262365.4	P0C5J1
FAM86B2	ENST00000942450.1		c.787A>C	p.Lys263Gln	missense	Exon 7 of 8	ENSP00000612509.1
FAM86B2	ENST00000870195.1		c.715A>C	p.Lys239Gln	missense	Exon 6 of 7	ENSP00000540254.1

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

GnomAD2 exomes

AF:

0.000501

AC:

AN:

161700

AF XY:

0.000558

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 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

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

African (AFR)

AF:

0.000116

AC:

AN:

25826

American (AMR)

AF:

0.000503

AC:

AN:

31830

Ashkenazi Jewish (ASJ)

AF:

0.0000626

AC:

AN:

15984

East Asian (EAS)

AF:

0.000593

AC:

AN:

30378

South Asian (SAS)

AF:

0.00238

AC:

154

AN:

64756

European-Finnish (FIN)

AF:

0.0000335

AC:

AN:

29852

Middle Eastern (MID)

AF:

0.00

AC:

AN:

2946

European-Non Finnish (NFE)

AF:

0.000957

AC:

722

AN:

754548

Other (OTH)

AF:

0.000692

AC:

AN:

41904

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.394

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

110

<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

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

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

African (AFR)

AF:

0.000153

AC:

AN:

26090

American (AMR)

AF:

0.000240

AC:

AN:

8316

Ashkenazi Jewish (ASJ)

AF:

0.00104

AC:

AN:

1920

East Asian (EAS)

AF:

0.00

AC:

AN:

3404

South Asian (SAS)

AF:

0.00261

AC:

AN:

2680

European-Finnish (FIN)

AF:

0.00

AC:

AN:

5390

Middle Eastern (MID)

AF:

0.00

AC:

AN:

176

European-Non Finnish (NFE)

AF:

0.000661

AC:

AN:

40818

Other (OTH)

AF:

0.00

AC:

AN:

1152

⚠️ The allele balance in gnomAD version 4 Genomes is significantly skewed from the expected value of 0.5. (p-value = 0.000362282), which strongly suggests a high chance of mosaicism in these individuals.

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.395

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:

0.00118

Hom.:

ExAC

AF:

0.000555

AC:

ClinVar

ClinVar submissions

Significance:Likely benign

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

0.064

BayesDel_addAF

Benign

-0.38

BayesDel_noAF

Benign

-0.78

CADD

Benign

0.86

(source)

DANN

Benign

0.21

DEOGEN2

Benign

0.0018

Eigen

Benign

-1.4

Eigen_PC

Benign

-1.5

FATHMM_MKL

Benign

0.0025

LIST_S2

Benign

0.10

M_CAP

Benign

0.0012

MetaRNN

Benign

0.0099

MetaSVM

Benign

-1.0

MutationAssessor

Benign

-0.48

PhyloP100

0.70

PrimateAI

Uncertain

0.55

PROVEAN

Benign

0.34

REVEL

Benign

0.013

Sift

Benign

1.0

Sift4G

Benign

0.64

Polyphen

0.0

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

Mutation Taster

=99/1

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