Genetic Variant FAIM2:p.Cys223Tyr (chr12-49889186-C-T) – ACMG Classification: Likely_benign (-4 pts)

Variant summary

Our verdict is Likely benign. The variant received -4 ACMG points: 0P and 4B. BP4_Strong

The NM_012306.4(FAIM2):c.668G>A(p.Cys223Tyr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000763 in 1,611,324 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 13/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. C223F) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.00043 ( 0 hom., cov: 32)

Exomes 𝑓: 0.000040 ( 0 hom. )

Consequence

FAIM2
NM_012306.4 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 2.04

Publications

1 publications found

Variant links:

Genes affected

FAIM2 (HGNC:17067): (Fas apoptotic inhibitory molecule 2) Involved in regulation of neuron apoptotic process. Acts upstream of or within negative regulation of extrinsic apoptotic signaling pathway via death domain receptors. Located in membrane raft. [provided by Alliance of Genome Resources, Apr 2022]

FAIM2 links:

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ACMG classification

Classification was made for transcript

Our verdict: Likely_benign. The variant received -4 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.038730115).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_012306.4. 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
	FAIM2	NM_012306.4	MANE Select	c.668G>A	p.Cys223Tyr	missense	Exon 10 of 12	NP_036438.2

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
FAIM2	ENST00000320634.8	TSL:1 MANE Select	c.668G>A	p.Cys223Tyr	missense	Exon 10 of 12	ENSP00000321951.3	Q9BWQ8-1
FAIM2	ENST00000947305.1		c.686G>A	p.Cys229Tyr	missense	Exon 10 of 12	ENSP00000617364.1
FAIM2	ENST00000947304.1		c.665G>A	p.Cys222Tyr	missense	Exon 10 of 12	ENSP00000617363.1

Frequencies

GnomAD3 genomes

AF:

0.000427

AC:

AN:

152196

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00154

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.000207

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00

Gnomad OTH

AF:

0.00

GnomAD2 exomes

AF:

0.000102

AC:

AN:

244832

AF XY:

0.0000605

show subpopulations

Gnomad AFR exome

AF:

0.00156

Gnomad AMR exome

AF:

0.0000294

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

AF:

0.0000398

AC:

AN:

1459010

Hom.:

Cov.:

AF XY:

0.0000358

AC XY:

AN XY:

725408

show subpopulations

African (AFR)

AF:

0.00161

AC:

AN:

33456

American (AMR)

AF:

0.0000451

AC:

AN:

44372

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26042

East Asian (EAS)

AF:

0.00

AC:

AN:

39642

South Asian (SAS)

AF:

0.00

AC:

AN:

85486

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53158

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5764

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

1110776

Other (OTH)

AF:

0.0000332

AC:

AN:

60314

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.452

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

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

GnomAD4 genome

AF:

0.000427

AC:

AN:

152314

Hom.:

Cov.:

AF XY:

0.000363

AC XY:

AN XY:

74482

show subpopulations

African (AFR)

AF:

0.00154

AC:

AN:

41570

American (AMR)

AF:

0.00

AC:

AN:

15306

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3472

East Asian (EAS)

AF:

0.00

AC:

AN:

5178

South Asian (SAS)

AF:

0.000207

AC:

AN:

4824

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10628

Middle Eastern (MID)

AF:

0.00

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

68014

Other (OTH)

AF:

0.00

AC:

AN:

2116

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.513

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

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:

0.000147

Hom.:

Bravo

AF:

0.000453

ESP6500AA

AF:

0.000908

AC:

ESP6500EA

AF:

0.00

AC:

ExAC

AF:

0.000132

AC:

ClinVar

ClinVar submissions

Significance:Uncertain significance

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

0.21

BayesDel_addAF

Benign

-0.42

BayesDel_noAF

Benign

-0.39

CADD

Benign

(source)

DANN

Uncertain

0.99

DEOGEN2

Benign

0.40

Eigen

Benign

-0.23

Eigen_PC

Benign

-0.067

FATHMM_MKL

Uncertain

0.82

LIST_S2

Uncertain

0.88

M_CAP

Benign

0.022

MetaRNN

Benign

0.039

MetaSVM

Benign

-1.1

MutationAssessor

Benign

0.89

PhyloP100

2.0

PrimateAI

Uncertain

0.72

PROVEAN

Pathogenic

-7.9

REVEL

Benign

0.19

Sift

Benign

0.064

Sift4G

Benign

0.22

Polyphen

0.0020

Vest4

0.32

MVP

0.29

MPC

0.65

ClinPred

0.089

GERP RS

4.6

Varity_R

0.64

gMVP

0.94

Mutation Taster

=81/19

polymorphism

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.030

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