chr1-15493953-G-T

Variant names:

• chr1-15493953-G-T
• rs61738967
• NM_001229.5:c.1097C>A

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The NM_001229.5(CASP9):​c.1097C>A​(p.Thr366Asn) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00189 in 1,604,750 control chromosomes in the GnomAD database, including 48 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0086 (19 hom., cov: 32)
  • Exomes 𝑓: 0.0012 (29 hom.)
• Consequence: CASP9 NM_001229.5 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: 2.60
• Publications: 4 publications found

Genes affected

CASP9 (HGNC:1511): (caspase 9) 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 which undergo proteolytic processing at conserved aspartic residues to produce two subunits, large and small, that dimerize to form the active enzyme. This protein can undergo autoproteolytic processing and activation by the apoptosome, a protein complex of cytochrome c and the apoptotic peptidase activating factor 1; this step is thought to be one of the earliest in the caspase activation cascade. This protein is thought to play a central role in apoptosis and to be a tumor suppressor. Alternative splicing results in multiple transcript variants. [provided by RefSeq, May 2013]

ACMG classification

Our verdict: Benign. The variant received -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.013510019).
• BP6: Variant 1-15493953-G-T is Benign according to our data. Variant chr1-15493953-G-T is described in ClinVar as Benign. ClinVar VariationId is 782360.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.00862 (1312/152232) while in subpopulation AFR AF = 0.0285 (1185/41526). AF 95% confidence interval is 0.0272. There are 19 homozygotes in GnomAd4. There are 625 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High AC in GnomAd4 at 1312 AD gene.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001229.5. 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
	CASP9	NM_001229.5	MANE Select	c.1097C>A	p.Thr366Asn	missense	Exon 8 of 9	NP_001220.2
	CASP9	NM_032996.3		c.848C>A	p.Thr283Asn	missense	Exon 8 of 9	NP_127463.2	P55211-4
	CASP9	NM_001278054.2		c.647C>A	p.Thr216Asn	missense	Exon 4 of 5	NP_001264983.1	P55211-2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CASP9	ENST00000333868.10	TSL:1 MANE Select	c.1097C>A	p.Thr366Asn	missense	Exon 8 of 9	ENSP00000330237.5	P55211-1
	CASP9	ENST00000348549.9	TSL:1	c.647C>A	p.Thr216Asn	missense	Exon 4 of 5	ENSP00000255256.7	P55211-2
	CASP9	ENST00000400777.7	TSL:1	n.*690C>A		non_coding_transcript_exon	Exon 8 of 9	ENSP00000383588.3	H0Y3S8

Frequencies

GnomAD3 genomes AF: 0.00862 AC: 1311 AN: 152114 Hom.: 19 Cov.: 32

Gnomad AFR AF: 0.0286

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00510

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00104

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000441

Gnomad OTH AF: 0.00718

GnomAD2 exomes AF: 0.00235 AC: 553 AN: 235386 AF XY: 0.00192

Gnomad AFR exome AF: 0.0269

Gnomad AMR exome AF: 0.00108

Gnomad ASJ exome AF: 0.000103

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000322

Gnomad OTH exome AF: 0.00205

GnomAD4 exome AF: 0.00118 AC: 1716 AN: 1452518 Hom.: 29 Cov.: 36 AF XY: 0.00112 AC XY: 810 AN XY: 721610

African (AFR) AF: 0.0282 AC: 937 AN: 33280

American (AMR) AF: 0.00151 AC: 66 AN: 43852

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25876

East Asian (EAS) AF: 0.00 AC: 0 AN: 39446

South Asian (SAS) AF: 0.00272 AC: 230 AN: 84642

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 52254

Middle Eastern (MID) AF: 0.00261 AC: 15 AN: 5758

European-Non Finnish (NFE) AF: 0.000301 AC: 333 AN: 1107348

Other (OTH) AF: 0.00225 AC: 135 AN: 60062

GnomAD4 genome AF: 0.00862 AC: 1312 AN: 152232 Hom.: 19 Cov.: 32 AF XY: 0.00840 AC XY: 625 AN XY: 74434

African (AFR) AF: 0.0285 AC: 1185 AN: 41526

American (AMR) AF: 0.00510 AC: 78 AN: 15306

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5170

South Asian (SAS) AF: 0.000830 AC: 4 AN: 4822

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10608

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.000441 AC: 30 AN: 68010

Other (OTH) AF: 0.00710 AC: 15 AN: 2112

Alfa AF: 0.00306 Hom.: 19

Bravo AF: 0.00988

TwinsUK AF: 0.000270 AC: 1

ALSPAC AF: 0.000259 AC: 1

ESP6500AA AF: 0.0234 AC: 103

ESP6500EA AF: 0.000233 AC: 2

ExAC AF: 0.00269 AC: 326

Asia WGS AF: 0.000866 AC: 3 AN: 3478

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	2	not provided (2)
-	-	1	CASP9-related disorder (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.18
BayesDel_addAF	Benign	-0.45	T
BayesDel_noAF	Benign	-0.40
CADD	Uncertain	23
DANN	Uncertain	0.99
DEOGEN2	Benign	0.19	T
Eigen	Uncertain	0.42
Eigen_PC	Uncertain	0.42
FATHMM_MKL	Uncertain	0.96	D
LIST_S2	Benign	0.85	T
MetaRNN	Benign	0.014	T
MetaSVM	Benign	-1.2	T
MutationAssessor	Uncertain	2.4	M
PhyloP100		2.6
PrimateAI	Uncertain	0.55	T
PROVEAN	Uncertain	-2.9	D
REVEL	Benign	0.17
Sift	Benign	0.13	T
Sift4G	Benign	0.10	T
Polyphen		0.88	P
Vest4		0.59
MVP		0.78
MPC		0.38
ClinPred		0.058	T
GERP RS		5.7
Varity_R		0.60
gMVP		0.71
Mutation Taster		=81/19	polymorphism

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: rs61738967; hg19: chr1-15820448; COSMIC: COSV99049509; COSMIC: COSV99049509;