2-201160828-G-C

Variant summary

Our verdict is Likely benign. Variant got -2 ACMG points: 0P and 2B. BP4_Moderate

The NM_003879.7(CFLAR):c.1190G>C(p.Arg397Pro) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000958 in 1,461,780 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: 31)
  • Exomes 𝑓: 0.0000096 (0 hom.)
• Consequence: CFLAR NM_003879.7 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.379

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]

ACMG classification

Verdict is Likely_benign. Variant got -2 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.108746886).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
CFLAR	NM_003879.7	c.1190G>C	p.Arg397Pro	missense_variant	9/10	ENST00000309955.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
CFLAR	ENST00000309955.8	c.1190G>C	p.Arg397Pro	missense_variant	9/10	1	NM_003879.7	P2

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD4 exome AF: 0.00000958 AC: 14 AN: 1461780 Hom.: 0 Cov.: 35 AF XY: 0.0000124 AC XY: 9 AN XY: 727196

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: 0.0000126

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 31

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Dec 26, 2023

The c.1190G>C (p.R397P) alteration is located in exon 9 (coding exon 8) of the CFLAR gene. This alteration results from a G to C substitution at nucleotide position 1190, causing the arginine (R) at amino acid position 397 to be replaced by a proline (P). 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	0.14
BayesDel_addAF	Benign	-0.22	T
BayesDel_noAF	Benign	-0.55
Cadd	Benign	11
Dann	Benign	0.83
DEOGEN2	Benign	0.070	T;.;.;T;.;.;T
Eigen	Benign	-0.99
Eigen_PC	Benign	-0.97
FATHMM_MKL	Benign	0.17	N
M_CAP	Benign	0.0056	T
MetaRNN	Benign	0.11	T;T;T;T;T;T;T
MetaSVM	Benign	-0.98	T
MutationAssessor	Benign	0.88	L;.;.;L;L;.;.
MutationTaster	Benign	1.0	N;N;N;N;N;N;N
PrimateAI	Benign	0.23	T
PROVEAN	Benign	-1.6	N;N;N;N;N;.;.
REVEL	Benign	0.034
Sift	Benign	0.20	T;T;T;T;T;.;.
Sift4G	Benign	0.26	T;T;T;T;T;T;T
Polyphen		0.016	B;.;B;B;B;B;.
Vest4		0.16
MutPred		0.69		Loss of MoRF binding (P = 0.0249);.;.;Loss of MoRF binding (P = 0.0249);Loss of MoRF binding (P = 0.0249);.;.;
MVP		0.32
MPC		0.47
ClinPred		0.042	T
GERP RS		1.0
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.66
gMVP		0.41

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

No publications associated with this variant yet.

Other links and lift over

hg19: chr2-202025551;