2-201298088-A-G

Variant names:

• chr2-201298088-A-G
• rs13016963
• NM_001127391.3:c.942+1150T>C

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_001127391.3(FLACC1):​c.942+1150T>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.597 in 151,894 control chromosomes in the GnomAD database, including 27,347 homozygotes. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency: Genomes: 𝑓 0.60 (27347 hom., cov: 30)
• Consequence: FLACC1 NM_001127391.3 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -1.21
• Publications: 68 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: Ambry Genetics, Labcorp Genetics (formerly Invitae), Orphanet

ACMG classification

Our verdict: Benign. The variant received -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.96).
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.74 is higher than 0.05.

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

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	FLACC1	NM_001127391.3	MANE Select	c.942+1150T>C		intron	N/A	NP_001120863.1
	FLACC1	NM_139163.4		c.942+1150T>C		intron	N/A	NP_631902.2
	FLACC1	NM_001289993.2		c.942+1150T>C		intron	N/A	NP_001276922.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	FLACC1	ENST00000392257.8	TSL:1 MANE Select	c.942+1150T>C		intron	N/A	ENSP00000376086.3
	FLACC1	ENST00000286190.9	TSL:1	c.942+1150T>C		intron	N/A	ENSP00000286190.5
	FLACC1	ENST00000405148.6	TSL:5	c.942+1150T>C		intron	N/A	ENSP00000385098.2

Frequencies

GnomAD3 genomes AF: 0.597 AC: 90548 AN: 151776 Hom.: 27315 Cov.: 30

Gnomad AFR AF: 0.567

Gnomad AMI AF: 0.727

Gnomad AMR AF: 0.483

Gnomad ASJ AF: 0.515

Gnomad EAS AF: 0.690

Gnomad SAS AF: 0.759

Gnomad FIN AF: 0.615

Gnomad MID AF: 0.576

Gnomad NFE AF: 0.622

Gnomad OTH AF: 0.571

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome AF: 0.597 AC: 90625 AN: 151894 Hom.: 27347 Cov.: 30 AF XY: 0.596 AC XY: 44286 AN XY: 74244

African (AFR) AF: 0.568 AC: 23507 AN: 41388

American (AMR) AF: 0.482 AC: 7350 AN: 15248

Ashkenazi Jewish (ASJ) AF: 0.515 AC: 1782 AN: 3462

East Asian (EAS) AF: 0.689 AC: 3548 AN: 5150

South Asian (SAS) AF: 0.761 AC: 3663 AN: 4816

European-Finnish (FIN) AF: 0.615 AC: 6493 AN: 10562

Middle Eastern (MID) AF: 0.575 AC: 169 AN: 294

European-Non Finnish (NFE) AF: 0.622 AC: 42253 AN: 67954

Other (OTH) AF: 0.568 AC: 1197 AN: 2108

Alfa AF: 0.615 Hom.: 109135

Bravo AF: 0.584

Asia WGS AF: 0.731 AC: 2542 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.96
CADD	Benign	0.24
DANN	Benign	0.52
PhyloP100		-1.2
Mutation Taster		=100/0	polymorphism (auto)

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

dbSNP: rs13016963; hg19: chr2-202162811;