chr2-201289477-C-T

Variant names:

• chr2-201289477-C-T
• rs17468277
• NM_001127391.3:c.1122G>A

Variant summary

Our verdict is Benign. The variant received -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BA1

The NM_001127391.3(FLACC1):​c.1122G>A​(p.Thr374Thr) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.115 in 1,613,772 control chromosomes in the GnomAD database, including 11,968 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.097 (810 hom., cov: 32)
  • Exomes 𝑓: 0.12 (11158 hom.)
• Consequence: FLACC1 NM_001127391.3 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -0.573
• Publications: 56 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 -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.78).
• BP6: Variant 2-201289477-C-T is Benign according to our data. Variant chr2-201289477-C-T is described in ClinVar as Benign. ClinVar VariationId is 402494.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=-0.573 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.128 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.1122G>A	p.Thr374Thr	synonymous	Exon 14 of 15	NP_001120863.1	Q96Q35-2
	FLACC1	NM_139163.4		c.1191G>A	p.Thr397Thr	synonymous	Exon 14 of 15	NP_631902.2	Q96Q35-1
	FLACC1	NM_001289993.2		c.1122G>A	p.Thr374Thr	synonymous	Exon 14 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.1122G>A	p.Thr374Thr	synonymous	Exon 14 of 15	ENSP00000376086.3	Q96Q35-2
	FLACC1	ENST00000286190.9	TSL:1	c.1191G>A	p.Thr397Thr	synonymous	Exon 13 of 14	ENSP00000286190.5	Q96Q35-1
	FLACC1	ENST00000405148.6	TSL:5	c.1191G>A	p.Thr397Thr	synonymous	Exon 14 of 15	ENSP00000385098.2	Q96Q35-1

Frequencies

GnomAD3 genomes AF: 0.0967 AC: 14711 AN: 152154 Hom.: 808 Cov.: 32

Gnomad AFR AF: 0.0622

Gnomad AMI AF: 0.271

Gnomad AMR AF: 0.0864

Gnomad ASJ AF: 0.0637

Gnomad EAS AF: 0.000384

Gnomad SAS AF: 0.0381

Gnomad FIN AF: 0.0979

Gnomad MID AF: 0.0791

Gnomad NFE AF: 0.130

Gnomad OTH AF: 0.108

GnomAD2 exomes AF: 0.0896 AC: 22515 AN: 251398 AF XY: 0.0891

Gnomad AFR exome AF: 0.0615

Gnomad AMR exome AF: 0.0571

Gnomad ASJ exome AF: 0.0606

Gnomad EAS exome AF: 0.000326

Gnomad FIN exome AF: 0.103

Gnomad NFE exome AF: 0.129

Gnomad OTH exome AF: 0.105

GnomAD4 exome AF: 0.117 AC: 171047 AN: 1461500 Hom.: 11158 Cov.: 32 AF XY: 0.115 AC XY: 83650 AN XY: 727064

African (AFR) AF: 0.0577 AC: 1931 AN: 33478

American (AMR) AF: 0.0601 AC: 2689 AN: 44722

Ashkenazi Jewish (ASJ) AF: 0.0646 AC: 1687 AN: 26132

East Asian (EAS) AF: 0.000202 AC: 8 AN: 39700

South Asian (SAS) AF: 0.0467 AC: 4028 AN: 86240

European-Finnish (FIN) AF: 0.106 AC: 5655 AN: 53402

Middle Eastern (MID) AF: 0.0836 AC: 482 AN: 5766

European-Non Finnish (NFE) AF: 0.133 AC: 147978 AN: 1111684

Other (OTH) AF: 0.109 AC: 6589 AN: 60376

GnomAD4 genome AF: 0.0968 AC: 14733 AN: 152272 Hom.: 810 Cov.: 32 AF XY: 0.0932 AC XY: 6942 AN XY: 74454

African (AFR) AF: 0.0627 AC: 2606 AN: 41548

American (AMR) AF: 0.0862 AC: 1318 AN: 15288

Ashkenazi Jewish (ASJ) AF: 0.0637 AC: 221 AN: 3472

East Asian (EAS) AF: 0.000385 AC: 2 AN: 5192

South Asian (SAS) AF: 0.0385 AC: 186 AN: 4826

European-Finnish (FIN) AF: 0.0979 AC: 1038 AN: 10606

Middle Eastern (MID) AF: 0.0680 AC: 20 AN: 294

European-Non Finnish (NFE) AF: 0.130 AC: 8870 AN: 68022

Other (OTH) AF: 0.107 AC: 225 AN: 2112

Alfa AF: 0.118 Hom.: 2256

Bravo AF: 0.0947

Asia WGS AF: 0.0270 AC: 94 AN: 3478

EpiCase AF: 0.129

EpiControl AF: 0.125

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

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

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.78
CADD	Benign	1.1
DANN	Benign	0.65
PhyloP100		-0.57
Mutation Taster		=100/0	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.12		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: rs17468277; hg19: chr2-202154200; COSMIC: COSV51860617; COSMIC: COSV51860617;