ENST00000557172.5:c.-2+867_-2+868insCCGCCG

Variant names:

• chr14-103562851-C-CCCGCCG
• rs28362583
• ENST00000557172.5:c.-2+867_-2+868insCCGCCG

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 2P and 4B. PM2 BS2

The ENST00000557172.5(KLC1):​c.-2+867_-2+868insCCGCCG variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000501 in 998,282 control chromosomes in the GnomAD database, with no homozygous occurrence. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: not found (cov: 26)
  • Exomes 𝑓: 0.0000050 (0 hom.)
• Consequence: KLC1 ENST00000557172.5 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.480
• Publications: 5 publications found

Genes affected

KLC1 (HGNC:6387): (kinesin light chain 1) Conventional kinesin is a tetrameric molecule composed of two heavy chains and two light chains, and transports various cargos along microtubules toward their plus ends. The heavy chains provide the motor activity, while the light chains bind to various cargos. This gene encodes a member of the kinesin light chain family. It associates with kinesin heavy chain through an N-terminal domain, and six tetratricopeptide repeat (TPR) motifs are thought to be involved in binding of cargos such as vesicles, mitochondria, and the Golgi complex. Thus, kinesin light chains function as adapter molecules and not motors per se. Although previously named "kinesin 2", this gene is not a member of the kinesin-2 / kinesin heavy chain subfamily of kinesin motor proteins. Extensive alternative splicing produces isoforms with different C-termini that are proposed to bind to different cargos; however, the full-length nature and/or biological validity of most of these variants have not been determined. [provided by RefSeq, Jul 2008]

BAG5 (HGNC:941): (BAG cochaperone 5) The protein encoded by this gene is a member of the BAG1-related protein family. BAG1 is an anti-apoptotic protein that functions through interactions with a variety of cell apoptosis and growth related proteins including BCL-2, Raf-protein kinase, steroid hormone receptors, growth factor receptors and members of the heat shock protein 70 kDa family. This protein contains a BAG domain near the C-terminus, which could bind and inhibit the chaperone activity of Hsc70/Hsp70. Three transcript variants encoding two different isoforms have been found for this gene. [provided by RefSeq, Jul 2008]

COA8 (HGNC:20492): (cytochrome c oxidase assembly factor 8) This gene encodes a protein that localizes to the mitochondria, where it stimulates the release of cytochrome c, thereby promoting programmed cell death. Mutations in this gene have been found in individuals with mitochondrial complex IV deficiency. Alternative splicing results in multiple transcript variants. [provided by RefSeq, Nov 2014]

COA8 Gene-Disease associations (from GenCC):

• mitochondrial complex IV deficiency, nuclear type 17

  Inheritance: AR Classification: DEFINITIVE, STRONG Submitted by: G2P, Labcorp Genetics (formerly Invitae)
• mitochondrial disease

  Inheritance: AR Classification: DEFINITIVE Submitted by: ClinGen
• non-progressive predominantly posterior cavitating leukoencephalopathy with peripheral neuropathy

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet

ENSG00000256500 (HGNC:):

ACMG classification

Our verdict: Likely_benign. The variant received -2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BS2: High AC in GnomAdExome4 at 5 AD gene.

Variant Effect in Transcripts

ACMG analysis was done for transcript: ENST00000557172.5. 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
	BAG5	NM_001015048.3	MANE Select	c.-265_-264insCGGCGG		upstream_gene	N/A	NP_001015048.1	A0A024R6M6
	COA8	NM_001370595.2	MANE Select	c.-151_-150insCCGCCG		upstream_gene	N/A	NP_001357524.1	A0A6Q8JUI0
	COA8	NM_001302653.2		c.-151_-150insCCGCCG		upstream_gene	N/A	NP_001289582.2	G3V4L6

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	KLC1	ENST00000557172.5	TSL:4	c.-2+867_-2+868insCCGCCG		intron	N/A	ENSP00000450786.1	G3V2P7
	BAG5	ENST00000299204.6	TSL:1 MANE Select	c.-265_-264insCGGCGG		upstream_gene	N/A	ENSP00000299204.4	Q9UL15-1
	COA8	ENST00000409074.8	TSL:1 MANE Select	c.-151_-150insCCGCCG		upstream_gene	N/A	ENSP00000386485.3	A0A6Q8JUI0

Frequencies

GnomAD3 genomes Cov.: 26

GnomAD4 exome AF: 0.00000501 AC: 5 AN: 998282 Hom.: 0 Cov.: 15 AF XY: 0.00000418 AC XY: 2 AN XY: 478736

African (AFR) AF: 0.00 AC: 0 AN: 19938

American (AMR) AF: 0.00 AC: 0 AN: 7450

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 13342

East Asian (EAS) AF: 0.0000846 AC: 2 AN: 23642

South Asian (SAS) AF: 0.00 AC: 0 AN: 28878

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 23898

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 2786

European-Non Finnish (NFE) AF: 0.00000358 AC: 3 AN: 837376

Other (OTH) AF: 0.00 AC: 0 AN: 40972

GnomAD4 genome Cov.: 26

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		-0.48

Splicing

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

Other links and lift over

dbSNP: rs28362583; hg19: chr14-104029188;