chr2-201289123-G-A

Variant names:

• chr2-201289123-G-A
• rs11674814
• NM_001127391.3:c.1142+334C>T

Variant summary

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

The NM_001127391.3(FLACC1):​c.1142+334C>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.338 in 152,108 control chromosomes in the GnomAD database, including 10,177 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 0.34 (10177 hom., cov: 33)
• Consequence: FLACC1 NM_001127391.3 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.0710
• Publications: 12 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: Benign. The variant received -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.88).
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.464 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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	FLACC1	NM_001127391.3	MANE Select	c.1142+334C>T		intron	N/A	NP_001120863.1	Q96Q35-2
	FLACC1	NM_139163.4		c.1211+334C>T		intron	N/A	NP_631902.2	Q96Q35-1
	FLACC1	NM_001289993.2		c.1142+334C>T		intron	N/A	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.1142+334C>T		intron	N/A	ENSP00000376086.3	Q96Q35-2
	FLACC1	ENST00000286190.9	TSL:1	c.1211+334C>T		intron	N/A	ENSP00000286190.5	Q96Q35-1
	FLACC1	ENST00000405148.6	TSL:5	c.1211+334C>T		intron	N/A	ENSP00000385098.2	Q96Q35-1

Frequencies

GnomAD3 genomes AF: 0.338 AC: 51405 AN: 151990 Hom.: 10181 Cov.: 33

Gnomad AFR AF: 0.122

Gnomad AMI AF: 0.390

Gnomad AMR AF: 0.324

Gnomad ASJ AF: 0.368

Gnomad EAS AF: 0.481

Gnomad SAS AF: 0.333

Gnomad FIN AF: 0.473

Gnomad MID AF: 0.316

Gnomad NFE AF: 0.440

Gnomad OTH AF: 0.323

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

GnomAD4 genome AF: 0.338 AC: 51389 AN: 152108 Hom.: 10177 Cov.: 33 AF XY: 0.339 AC XY: 25190 AN XY: 74340

African (AFR) AF: 0.121 AC: 5033 AN: 41520

American (AMR) AF: 0.323 AC: 4936 AN: 15280

Ashkenazi Jewish (ASJ) AF: 0.368 AC: 1276 AN: 3468

East Asian (EAS) AF: 0.480 AC: 2475 AN: 5154

South Asian (SAS) AF: 0.332 AC: 1599 AN: 4810

European-Finnish (FIN) AF: 0.473 AC: 5000 AN: 10570

Middle Eastern (MID) AF: 0.330 AC: 97 AN: 294

European-Non Finnish (NFE) AF: 0.440 AC: 29937 AN: 67988

Other (OTH) AF: 0.322 AC: 681 AN: 2114

Alfa AF: 0.375 Hom.: 1852

Bravo AF: 0.321

Asia WGS AF: 0.380 AC: 1321 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.88
CADD	Benign	2.9
DANN	Benign	0.55
PhyloP100		0.071
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: rs11674814; hg19: chr2-202153846;