chr2-201289066-C-T

Variant names:

• chr2-201289066-C-T
• rs17383714
• NM_001127391.3:c.1143-285G>A

Variant summary

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

The NM_001127391.3(FLACC1):​c.1143-285G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0634 in 152,278 control chromosomes in the GnomAD database, including 422 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 0.063 (422 hom., cov: 33)
• Consequence: FLACC1 NM_001127391.3 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.0280
• Publications: 3 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=-0.81).
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.0872 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.1143-285G>A		intron	N/A	NP_001120863.1
	FLACC1	NM_139163.4		c.1212-285G>A		intron	N/A	NP_631902.2
	FLACC1	NM_001289993.2		c.1143-285G>A		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.1143-285G>A		intron	N/A	ENSP00000376086.3
	FLACC1	ENST00000286190.9	TSL:1	c.1212-285G>A		intron	N/A	ENSP00000286190.5
	FLACC1	ENST00000405148.6	TSL:5	c.1212-285G>A		intron	N/A	ENSP00000385098.2

Frequencies

GnomAD3 genomes AF: 0.0635 AC: 9659 AN: 152160 Hom.: 424 Cov.: 33

Gnomad AFR AF: 0.0150

Gnomad AMI AF: 0.0208

Gnomad AMR AF: 0.0597

Gnomad ASJ AF: 0.132

Gnomad EAS AF: 0.000770

Gnomad SAS AF: 0.0944

Gnomad FIN AF: 0.0868

Gnomad MID AF: 0.114

Gnomad NFE AF: 0.0891

Gnomad OTH AF: 0.0828

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

GnomAD4 genome AF: 0.0634 AC: 9654 AN: 152278 Hom.: 422 Cov.: 33 AF XY: 0.0640 AC XY: 4762 AN XY: 74442

African (AFR) AF: 0.0150 AC: 622 AN: 41564

American (AMR) AF: 0.0596 AC: 913 AN: 15306

Ashkenazi Jewish (ASJ) AF: 0.132 AC: 458 AN: 3472

East Asian (EAS) AF: 0.000772 AC: 4 AN: 5184

South Asian (SAS) AF: 0.0941 AC: 454 AN: 4826

European-Finnish (FIN) AF: 0.0868 AC: 920 AN: 10594

Middle Eastern (MID) AF: 0.109 AC: 32 AN: 294

European-Non Finnish (NFE) AF: 0.0891 AC: 6059 AN: 68014

Other (OTH) AF: 0.0819 AC: 173 AN: 2112

Alfa AF: 0.0833 Hom.: 322

Bravo AF: 0.0567

Asia WGS AF: 0.0360 AC: 127 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.81
CADD	Benign	1.5
DANN	Benign	0.49
PhyloP100		-0.028
Mutation Taster		=100/0	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs17383714; hg19: chr2-202153789;