NM_001127391.3:c.1252A>G

Variant names:

• chr2-201288672-T-C
• NM_001127391.3:c.1252A>G

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 2P and 4B. PM2 BP4_Strong

The NM_001127391.3(FLACC1):​c.1252A>G​(p.Lys418Glu) 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. 16/22 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: FLACC1 NM_001127391.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: -0.117
• Publications: 0 publications found

Genes affected

FLACC1 (HGNC:14439): (flagellum associated containing coiled-coil domains 1) Predicted to be located in cytoplasmic vesicle and sperm flagellum. Predicted to be active in cytoplasm; outer dense fiber; and sperm fibrous sheath. [provided by Alliance of Genome Resources, Apr 2022]

CASP8 (HGNC:1509): (caspase 8) This gene encodes a member of the cysteine-aspartic acid protease (caspase) family. Sequential activation of caspases plays a central role in the execution-phase of cell apoptosis. Caspases exist as inactive proenzymes composed of a prodomain, a large protease subunit, and a small protease subunit. Activation of caspases requires proteolytic processing at conserved internal aspartic residues to generate a heterodimeric enzyme consisting of the large and small subunits. This protein is involved in the programmed cell death induced by Fas and various apoptotic stimuli. The N-terminal FADD-like death effector domain of this protein suggests that it may interact with Fas-interacting protein FADD. This protein was detected in the insoluble fraction of the affected brain region from Huntington disease patients but not in those from normal controls, which implicated the role in neurodegenerative diseases. Many alternatively spliced transcript variants encoding different isoforms have been described, although not all variants have had their full-length sequences determined. [provided by RefSeq, Jul 2008]

CASP8 Gene-Disease associations (from GenCC):

• autoimmune lymphoproliferative syndrome type 2B

  Inheritance: AR Classification: STRONG, MODERATE, SUPPORTIVE Submitted by: Orphanet, Ambry Genetics, Labcorp Genetics (formerly Invitae)

ACMG classification

Our verdict: Likely_benign. The variant received -2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.059766024).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001127391.3. 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
	FLACC1	NM_001127391.3	MANE Select	c.1252A>G	p.Lys418Glu	missense	Exon 15 of 15	NP_001120863.1	Q96Q35-2
	FLACC1	NM_139163.4		c.1321A>G	p.Lys441Glu	missense	Exon 15 of 15	NP_631902.2	Q96Q35-1
	FLACC1	NM_001289993.2		c.1252A>G	p.Lys418Glu	missense	Exon 15 of 15	NP_001276922.1	Q96Q35-2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	FLACC1	ENST00000392257.8	TSL:1 MANE Select	c.1252A>G	p.Lys418Glu	missense	Exon 15 of 15	ENSP00000376086.3	Q96Q35-2
	FLACC1	ENST00000286190.9	TSL:1	c.1321A>G	p.Lys441Glu	missense	Exon 14 of 14	ENSP00000286190.5	Q96Q35-1
	FLACC1	ENST00000405148.6	TSL:5	c.1321A>G	p.Lys441Glu	missense	Exon 15 of 15	ENSP00000385098.2	Q96Q35-1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 30

GnomAD4 genome Cov.: 32

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.073
BayesDel_addAF	Benign	-0.32	T
BayesDel_noAF	Benign	-0.70
CADD	Benign	4.6
DANN	Benign	0.82
DEOGEN2	Benign	0.025	T
Eigen	Benign	-1.1
Eigen_PC	Benign	-1.1
FATHMM_MKL	Benign	0.024	N
LIST_S2	Benign	0.34	T
M_CAP	Benign	0.0018	T
MetaRNN	Benign	0.060	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	0.52	N
PhyloP100		-0.12
PrimateAI	Benign	0.31	T
PROVEAN	Benign	-0.88	N
REVEL	Benign	0.016
Sift	Benign	0.30	T
Sift4G	Benign	0.51	T
Polyphen		0.019	B
Vest4		0.026
MutPred		0.12		Loss of ubiquitination at K441 (P = 0.0039)
MVP		0.30
MPC		0.044
ClinPred		0.037	T
GERP RS		2.0
Varity_R		0.073
gMVP		0.0050
Mutation Taster		=95/5	polymorphism

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

Other links and lift over

hg19: chr2-202153395;