2-201149051-A-C

Variant names:

• chr2-201149051-A-C
• NM_003879.7:c.710A>C

Variant summary

Our verdict is Uncertain significance. The variant received 2 ACMG points: 2P and 0B. PM2

The NM_003879.7(CFLAR):​c.710A>C​(p.Gln237Pro) variant causes a missense, splice region 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. 16/26 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)
• Consequence: CFLAR NM_003879.7 missense, splice_region
• Scores: Splicing: ADA: 0.9857
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: -0.338
• Publications: 0 publications found

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

ACMG classification

Our verdict: Uncertain_significance. The variant received 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CFLAR	NM_003879.7	c.710A>C	p.Gln237Pro	missense_variant, splice_region_variant	Exon 7 of 10	ENST00000309955.8	NP_003870.4

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CFLAR	ENST00000309955.8	c.710A>C	p.Gln237Pro	missense_variant, splice_region_variant	Exon 7 of 10	1	NM_003879.7	ENSP00000312455.2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 26

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Mar 22, 2025

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.710A>C (p.Q237P) alteration is located in exon 7 (coding exon 6) of the CFLAR gene. This alteration results from a A to C substitution at nucleotide position 710, causing the glutamine (Q) at amino acid position 237 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	0.065
BayesDel_addAF	Benign	-0.15	T
BayesDel_noAF	Benign	-0.45
CADD	Benign	15
DANN	Benign	0.95
DEOGEN2	Benign	0.12	T;.;.;T;.;.;.;T
Eigen	Benign	-0.77
Eigen_PC	Benign	-0.70
FATHMM_MKL	Benign	0.28	N
LIST_S2	Benign	0.81	.;T;T;T;T;T;T;T
M_CAP	Benign	0.0067	T
MetaRNN	Benign	0.073	T;T;T;T;T;T;T;T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	1.7	L;.;L;L;L;.;.;.
PhyloP100		-0.34
PrimateAI	Benign	0.22	T
PROVEAN	Benign	-1.5	N;N;N;N;N;.;.;.
REVEL	Benign	0.079
Sift	Benign	0.20	T;T;T;T;T;.;.;.
Sift4G	Benign	0.13	T;T;T;T;T;T;T;T
Polyphen		0.017	B;.;B;B;B;.;B;.
Vest4		0.17
MutPred		0.27		Gain of catalytic residue at P236 (P = 0.0107);.;Gain of catalytic residue at P236 (P = 0.0107);Gain of catalytic residue at P236 (P = 0.0107);Gain of catalytic residue at P236 (P = 0.0107);.;.;.;
MVP		0.50
MPC		0.38
ClinPred		0.074	T
GERP RS		-1.5
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		2.8
Varity_R		0.22
gMVP		0.68
Mutation Taster		=88/12	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Pathogenic	0.99
dbscSNV1_RF	Benign	0.69
SpliceAI score (max)		0.36		Details are displayed if max score is > 0.2
DS_DL_spliceai		0.36		Position offset: 1

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

Other links and lift over

hg19: chr2-202013774;