rs11267038

Variant names:

• chr7-25124125-A-C
• rs11267038
• NM_018947.6:c.-6T>G

Variant summary

Our verdict is Benign. The variant received -16 ACMG points: 0P and 16B. BP6_Very_Strong BA1

The NM_018947.6(CYCS):​c.-6T>G variant causes a splice region change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.049 in 1,611,606 control chromosomes in the GnomAD database, including 2,311 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.040 (167 hom., cov: 33)
  • Exomes 𝑓: 0.050 (2144 hom.)
• Consequence: CYCS NM_018947.6 splice_region
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: 0.696
• Publications: 5 publications found

Genes affected

CYCS (HGNC:19986): (cytochrome c, somatic) This gene encodes a small heme protein that functions as a central component of the electron transport chain in mitochondria. The encoded protein associates with the inner membrane of the mitochondrion where it accepts electrons from cytochrome b and transfers them to the cytochrome oxidase complex. This protein is also involved in initiation of apoptosis. Mutations in this gene are associated with autosomal dominant nonsyndromic thrombocytopenia. Numerous processed pseudogenes of this gene are found throughout the human genome.[provided by RefSeq, Jul 2010]

CYCS Gene-Disease associations (from GenCC):

• thrombocytopenia 4

  Inheritance: AD Classification: STRONG, MODERATE, LIMITED Submitted by: Ambry Genetics, ClinGen, Labcorp Genetics (formerly Invitae)
• autosomal thrombocytopenia with normal platelets

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet

ENSG00000296268 (HGNC:):

ACMG classification

Our verdict: Benign. The variant received -16 ACMG points.

• BP6: Variant 7-25124125-A-C is Benign according to our data. Variant chr7-25124125-A-C is described in ClinVar as Benign. ClinVar VariationId is 261063.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.058 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_018947.6. 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
	CYCS	NM_018947.6	MANE Select	c.-6T>G		splice_region	Exon 2 of 3	NP_061820.1	G4XXL9
	CYCS	NM_018947.6	MANE Select	c.-6T>G		5_prime_UTR	Exon 2 of 3	NP_061820.1	G4XXL9

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CYCS	ENST00000305786.7	TSL:1 MANE Select	c.-6T>G		splice_region	Exon 2 of 3	ENSP00000307786.2	P99999
	CYCS	ENST00000305786.7	TSL:1 MANE Select	c.-6T>G		5_prime_UTR	Exon 2 of 3	ENSP00000307786.2	P99999
	CYCS	ENST00000409409.5	TSL:3	c.-6T>G		splice_region	Exon 2 of 3	ENSP00000386270.1	P99999

Frequencies

GnomAD3 genomes AF: 0.0400 AC: 6084 AN: 152090 Hom.: 167 Cov.: 33

Gnomad AFR AF: 0.0109

Gnomad AMI AF: 0.0758

Gnomad AMR AF: 0.0257

Gnomad ASJ AF: 0.00865

Gnomad EAS AF: 0.000384

Gnomad SAS AF: 0.00477

Gnomad FIN AF: 0.0960

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0595

Gnomad OTH AF: 0.0258

GnomAD2 exomes AF: 0.0399 AC: 9888 AN: 247572 AF XY: 0.0399

Gnomad AFR exome AF: 0.00937

Gnomad AMR exome AF: 0.0163

Gnomad ASJ exome AF: 0.00749

Gnomad EAS exome AF: 0.000218

Gnomad FIN exome AF: 0.0905

Gnomad NFE exome AF: 0.0602

Gnomad OTH exome AF: 0.0360

GnomAD4 exome AF: 0.0499 AC: 72870 AN: 1459398 Hom.: 2144 Cov.: 31 AF XY: 0.0488 AC XY: 35404 AN XY: 726172

African (AFR) AF: 0.00753 AC: 252 AN: 33458

American (AMR) AF: 0.0169 AC: 755 AN: 44714

Ashkenazi Jewish (ASJ) AF: 0.00853 AC: 223 AN: 26128

East Asian (EAS) AF: 0.000101 AC: 4 AN: 39696

South Asian (SAS) AF: 0.00808 AC: 697 AN: 86230

European-Finnish (FIN) AF: 0.0895 AC: 4659 AN: 52060

Middle Eastern (MID) AF: 0.00399 AC: 23 AN: 5762

European-Non Finnish (NFE) AF: 0.0574 AC: 63771 AN: 1111012

Other (OTH) AF: 0.0412 AC: 2486 AN: 60338

GnomAD4 genome AF: 0.0400 AC: 6085 AN: 152208 Hom.: 167 Cov.: 33 AF XY: 0.0404 AC XY: 3007 AN XY: 74422

African (AFR) AF: 0.0109 AC: 452 AN: 41530

American (AMR) AF: 0.0257 AC: 393 AN: 15288

Ashkenazi Jewish (ASJ) AF: 0.00865 AC: 30 AN: 3468

East Asian (EAS) AF: 0.000385 AC: 2 AN: 5190

South Asian (SAS) AF: 0.00477 AC: 23 AN: 4818

European-Finnish (FIN) AF: 0.0960 AC: 1016 AN: 10580

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

European-Non Finnish (NFE) AF: 0.0595 AC: 4046 AN: 68016

Other (OTH) AF: 0.0255 AC: 54 AN: 2114

Alfa AF: 0.0431 Hom.: 193

Bravo AF: 0.0327

Asia WGS AF: 0.00433 AC: 16 AN: 3478

EpiCase AF: 0.0500

EpiControl AF: 0.0468

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	1	not provided (1)
-	-	1	not specified (1)
-	-	1	Thrombocytopenia 4 (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.71
CADD	Benign	17
DANN	Benign	0.85
PhyloP100		0.70
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Mutation Taster		=300/0	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.28		Details are displayed if max score is > 0.2
DS_AG_spliceai		0.28		Position offset: -1

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs11267038; hg19: chr7-25163744;