chr2-201160737-C-G

Position:

• chr2-201160737-C-G

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_003879.7(CFLAR):​c.1099C>G​(p.Leu367Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 14/21 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)
• Consequence: CFLAR NM_003879.7 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.238

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 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=0.09042457).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
CFLAR	NM_003879.7	c.1099C>G	p.Leu367Val	missense_variant	9/10	ENST00000309955.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
CFLAR	ENST00000309955.8	c.1099C>G	p.Leu367Val	missense_variant	9/10	1	NM_003879.7	P2

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD4 exome Cov.: 36

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

Aug 16, 2022

The c.1099C>G (p.L367V) alteration is located in exon 9 (coding exon 8) of the CFLAR gene. This alteration results from a C to G substitution at nucleotide position 1099, causing the leucine (L) at amino acid position 367 to be replaced by a valine (V). 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	0.074
BayesDel_addAF	Benign	-0.28	T
BayesDel_noAF	Benign	-0.64
CADD	Benign	12
DANN	Uncertain	0.97
DEOGEN2	Benign	0.034	T;.;.;T;.;.;T
Eigen	Benign	-0.65
Eigen_PC	Benign	-0.73
FATHMM_MKL	Benign	0.14	N
LIST_S2	Benign	0.76	.;T;T;T;T;T;T
M_CAP	Benign	0.0070	T
MetaRNN	Benign	0.090	T;T;T;T;T;T;T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	1.7	L;.;.;L;L;.;.
MutationTaster	Benign	1.0	N;N;N;N;N;N;N
PrimateAI	Benign	0.22	T
PROVEAN	Benign	-0.27	N;N;N;N;N;.;.
REVEL	Benign	0.082
Sift	Benign	0.29	T;T;T;T;T;.;.
Sift4G	Benign	0.34	T;T;T;T;T;T;T
Polyphen		0.32	B;.;B;B;B;B;.
Vest4		0.087
MutPred		0.49		Loss of sheet (P = 0.0457);.;.;Loss of sheet (P = 0.0457);Loss of sheet (P = 0.0457);.;.;
MVP		0.56
MPC		0.49
ClinPred		0.17	T
GERP RS		-1.8
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.043
gMVP		0.16

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

Other links and lift over

dbSNP: rs1942891566; hg19: chr2-202025460;