chr2-201340474-C-T

Variant names:

• chr2-201340474-C-T
• rs10185177
• NM_001127391.3:c.524+1896G>A

Variant summary

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

The ENST00000392257.8(FLACC1):​c.524+1896G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.212 in 152,086 control chromosomes in the GnomAD database, including 5,424 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 0.21 (5424 hom., cov: 32)
• Consequence: FLACC1 ENST00000392257.8 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.921
• Publications: 7 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=-0.97).
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.455 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: ENST00000392257.8. 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.524+1896G>A		intron	N/A	NP_001120863.1
	FLACC1	NM_139163.4		c.524+1896G>A		intron	N/A	NP_631902.2
	FLACC1	NM_001289993.2		c.524+1896G>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.524+1896G>A		intron	N/A	ENSP00000376086.3
	FLACC1	ENST00000286190.9	TSL:1	c.524+1896G>A		intron	N/A	ENSP00000286190.5
	FLACC1	ENST00000405148.6	TSL:5	c.524+1896G>A		intron	N/A	ENSP00000385098.2

Frequencies

GnomAD3 genomes AF: 0.211 AC: 32122 AN: 151968 Hom.: 5393 Cov.: 32

Gnomad AFR AF: 0.460

Gnomad AMI AF: 0.0658

Gnomad AMR AF: 0.140

Gnomad ASJ AF: 0.144

Gnomad EAS AF: 0.256

Gnomad SAS AF: 0.250

Gnomad FIN AF: 0.0361

Gnomad MID AF: 0.196

Gnomad NFE AF: 0.103

Gnomad OTH AF: 0.188

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

GnomAD4 genome AF: 0.212 AC: 32203 AN: 152086 Hom.: 5424 Cov.: 32 AF XY: 0.210 AC XY: 15645 AN XY: 74366

African (AFR) AF: 0.461 AC: 19090 AN: 41424

American (AMR) AF: 0.140 AC: 2140 AN: 15284

Ashkenazi Jewish (ASJ) AF: 0.144 AC: 500 AN: 3466

East Asian (EAS) AF: 0.257 AC: 1328 AN: 5176

South Asian (SAS) AF: 0.250 AC: 1205 AN: 4822

European-Finnish (FIN) AF: 0.0361 AC: 383 AN: 10608

Middle Eastern (MID) AF: 0.197 AC: 58 AN: 294

European-Non Finnish (NFE) AF: 0.103 AC: 7029 AN: 67988

Other (OTH) AF: 0.194 AC: 410 AN: 2112

Alfa AF: 0.115 Hom.: 1212

Bravo AF: 0.227

Asia WGS AF: 0.283 AC: 980 AN: 3466

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.97
CADD	Benign	1.0
DANN	Benign	0.29
PhyloP100		-0.92
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: rs10185177; hg19: chr2-202205197;