7-25123714-GCTT-G

Variant summary

Our verdict is Uncertain significance. Variant got 5 ACMG points: 5P and 0B. PM1 PM2 PM4_Supporting

The NM_018947.6(CYCS):c.302_304del(p.Lys101_Ala102delinsThr) variant causes a inframe deletion change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 33)
• Consequence: CYCS NM_018947.6 inframe_deletion
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 3.56

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]

ACMG classification

Verdict is Uncertain_significance. Variant got 5 ACMG points.

• PM1: In a helix (size 13) in uniprot entity CYC_HUMAN there are 4 pathogenic changes around while only 0 benign (100%) in NM_018947.6
• PM2: Very rare variant in population databases, with high coverage
• PM4: Nonframeshift variant in NON repetitive region in NM_018947.6. Strenght limited to Supporting due to length of the change: 1aa.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
CYCS	NM_018947.6	c.302_304del	p.Lys101_Ala102delinsThr	inframe_deletion	3/3	ENST00000305786.7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
CYCS	ENST00000305786.7	c.302_304del	p.Lys101_Ala102delinsThr	inframe_deletion	3/3	1	NM_018947.6	P1
CYCS	ENST00000409409.5	c.302_304del	p.Lys101_Ala102delinsThr	inframe_deletion	3/3	3		P1
CYCS	ENST00000409764.5	c.302_304del	p.Lys101_Ala102delinsThr	inframe_deletion	4/4	3		P1
CYCS	ENST00000413447.1			coding_sequence_variant, 3_prime_UTR_variant	4/4	3

Frequencies

GnomAD3 genomes Cov.: 33

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

GnomAD4 genome Cov.: 33

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Invitae

Dec 11, 2023

This variant, c.302_304del, is a complex sequence change that results in the deletion of 2 and insertion of 1 amino acid(s) in the CYCS protein (p.Lys101_Ala102delinsThr). This variant is not present in population databases (gnomAD no frequency). This variant has not been reported in the literature in individuals affected with CYCS-related conditions. Experimental studies and prediction algorithms are not available or were not evaluated, and the functional significance of this variant is currently unknown. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. -

Computational scores

Source: dbNSFP v4.3

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

Publications

No publications associated with this variant yet.

Other links and lift over

hg19: chr7-25163333;