8-12428761-C-A

Variant names:

• chr8-12428761-C-A
• rs758719069
• NM_001137610.3:c.614G>T

Variant summary

Our verdict is Uncertain significance. The variant received 1 ACMG points: 1P and 0B. PP3

The NM_001137610.3(FAM86B2):​c.614G>T​(p.Gly205Val) variant causes a missense change. In-silico tool predicts a pathogenic outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. G205D) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 18)
  • Exomes 𝑓: 9.6e-7 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: FAM86B2 NM_001137610.3 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 3.68
• Publications: 0 publications found

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]

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

ACMG classification

Our verdict: Uncertain_significance. The variant received 1 ACMG points.

• PP3: MetaRNN computational evidence supports a deleterious effect, 0.831

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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	FAM86B2	NM_001137610.3	MANE Select	c.614G>T	p.Gly205Val	missense	Exon 6 of 8	NP_001131082.1	P0C5J1
	FAM86B2	NR_148876.2		n.431+220G>T		intron	N/A
	FAM86B2	NR_148877.2		n.350+220G>T		intron	N/A

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	FAM86B2	ENST00000262365.9	TSL:5 MANE Select	c.614G>T	p.Gly205Val	missense	Exon 6 of 8	ENSP00000262365.4	P0C5J1
	FAM86B2	ENST00000942450.1		c.584G>T	p.Gly195Val	missense	Exon 6 of 8	ENSP00000612509.1
	FAM86B2	ENST00000870195.1		c.512G>T	p.Gly171Val	missense	Exon 5 of 7	ENSP00000540254.1

Frequencies

GnomAD3 genomes Cov.: 18

GnomAD2 exomes AF: 0.00000700 AC: 1 AN: 142898 AF XY: 0.0000130

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.0000476

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome Data not reliable, filtered out with message: AS_VQSR AF: 9.58e-7 AC: 1 AN: 1044030 Hom.: 0 Cov.: 30 AF XY: 0.00000190 AC XY: 1 AN XY: 525430

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

African (AFR) AF: 0.00 AC: 0 AN: 22918

American (AMR) AF: 0.0000293 AC: 1 AN: 34140

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 20370

East Asian (EAS) AF: 0.00 AC: 0 AN: 34342

South Asian (SAS) AF: 0.00 AC: 0 AN: 67014

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 38744

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 3200

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 777394

Other (OTH) AF: 0.00 AC: 0 AN: 45908

⚠️ 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.

GnomAD4 genome Cov.: 18

Alfa AF: 0.00 Hom.: 0

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.19
BayesDel_addAF	Benign	-0.093	T
BayesDel_noAF	Benign	-0.37
CADD	Benign	23
DANN	Uncertain	0.99
DEOGEN2	Benign	0.032	T
Eigen	Benign	-0.071
Eigen_PC	Benign	-0.32
FATHMM_MKL	Uncertain	0.92	D
LIST_S2	Uncertain	0.91	D
M_CAP	Benign	0.0080	T
MetaRNN	Pathogenic	0.83	D
MetaSVM	Benign	-0.98	T
MutationAssessor	Uncertain	2.6	M
PhyloP100		3.7
PrimateAI	Uncertain	0.60	T
PROVEAN	Pathogenic	-6.2	D
REVEL	Benign	0.20
Sift	Uncertain	0.018	D
Sift4G	Benign	0.11	T
Polyphen		0.96	D
Vest4		0.66
MutPred		0.76		Loss of catalytic residue at G205 (P = 0.1204)
MVP		0.36
MPC		3.4
ClinPred		0.98	D
GERP RS		0.22
Varity_R		0.56
gMVP		0.67
Mutation Taster		=88/12	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.090		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs758719069; hg19: chr8-12286270;