Variant chr2-201140403-C-G details in Genebe, Genetics Data Aggregator

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2BP4_Moderate

The NM_003879.7(CFLAR):c.570C>G(p.Ile190Met) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000686 in 1,458,168 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: not found (cov: 32)

Exomes 𝑓: 6.9e-7 ( 0 hom. )

Consequence

CFLAR
NM_003879.7 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: -0.179

Variant links:

Genes affected

CFLAR (HGNC:1876): (CASP8 and FADD like apoptosis regulator) The protein encoded by this gene is a regulator of apoptosis and is structurally similar to caspase-8. However, the encoded protein lacks caspase activity and appears to be itself cleaved into two peptides by caspase-8. Several transcript variants encoding different isoforms have been found for this gene, and partial evidence for several more variants exists. [provided by RefSeq, Feb 2011]

CFLAR links:

CFLAR-AS1 (HGNC:14437): (CFLAR antisense RNA 1)

CFLAR-AS1 links:

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ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 0 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.087038785).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
CFLAR	NM_003879.7 linkuse as main transcript	c.570C>G	p.Ile190Met	missense_variant	5/10	ENST00000309955.8	NP_003870.4
CFLAR-AS1	NR_040030.1 linkuse as main transcript	n.927G>C		non_coding_transcript_exon_variant	7/7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
CFLAR	ENST00000309955.8 linkuse as main transcript	c.570C>G	p.Ile190Met	missense_variant	5/10	1	NM_003879.7	ENSP00000312455	P2	O15519-1
CFLAR-AS1	ENST00000415011.6 linkuse as main transcript	n.958G>C		non_coding_transcript_exon_variant	7/7	1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

6.86e-7

AC:

AN:

1458168

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

725486

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:

9.00e-7

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

Cov.:

Bravo

AF:

0.00000378

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Dec 06, 2022

The c.570C>G (p.I190M) alteration is located in exon 5 (coding exon 4) of the CFLAR gene. This alteration results from a C to G substitution at nucleotide position 570, causing the isoleucine (I) at amino acid position 190 to be replaced by a methionine (M). 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

0.080

BayesDel_addAF

Benign

-0.14

BayesDel_noAF

Benign

-0.44

CADD

Benign

8.3

DANN

Benign

0.82

DEOGEN2

Benign

0.089

T;.;.;.;.;T;.;.;T;T;.;.;T

Eigen

Benign

-0.73

Eigen_PC

Benign

-0.79

FATHMM_MKL

Benign

0.084

LIST_S2

Uncertain

0.87

.;D;.;D;D;D;D;D;D;D;D;D;D

M_CAP

Benign

0.044

MetaRNN

Benign

0.087

T;T;T;T;T;T;T;T;T;T;T;T;T

MetaSVM

Benign

-0.74

MutationAssessor

Benign

0.0

N;.;N;N;N;N;N;N;.;.;.;.;.

MutationTaster

Benign

1.0

N;N;N;N;N;N;N;N;N;N

PrimateAI

Benign

0.30

PROVEAN

Benign

-0.25

N;N;N;N;N;N;N;N;.;.;.;.;.

REVEL

Benign

0.033

Sift

Benign

0.22

T;D;T;T;T;T;T;T;.;.;.;.;.

Sift4G

Benign

0.13

T;T;T;T;T;T;T;T;D;T;T;T;T

Polyphen

0.43

B;.;P;P;B;B;P;P;.;.;.;B;.

Vest4

0.15

MutPred

0.30

Gain of disorder (P = 0.0444);.;Gain of disorder (P = 0.0444);Gain of disorder (P = 0.0444);Gain of disorder (P = 0.0444);Gain of disorder (P = 0.0444);Gain of disorder (P = 0.0444);Gain of disorder (P = 0.0444);.;.;.;.;.;

MVP

0.56

MPC

0.36

ClinPred

0.12

GERP RS

2.0

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.1

Varity_R

0.031

gMVP

0.23

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