14-103562851-CCCG-CCCGCCG

Variant names:

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

Variant summary

Our verdict is Benign. The variant received -10 ACMG points: 0P and 10B. BP6_Moderate BA1

The ENST00000557172.5(KLC1):​c.-2+867_-2+868insCCG variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.26 in 1,146,862 control chromosomes in the GnomAD database, including 40,974 homozygotes. Variant has been reported in ClinVar as Benign (★).

• Frequency:
  • Genomes: 𝑓 0.24 (4970 hom., cov: 26)
  • Exomes 𝑓: 0.26 (36004 hom.)
• Consequence: KLC1 ENST00000557172.5 intron
• Clinical Significance: Benign criteria provided, single submitter B:1
• 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: Benign. The variant received -10 ACMG points.

• BP6: Variant 14-103562851-C-CCCG is Benign according to our data. Variant chr14-103562851-C-CCCG is described in ClinVar as Benign. ClinVar VariationId is 1244059.Status of the report is criteria_provided_single_submitter, 1 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.333 is higher than 0.05.

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_-264insCGG		upstream_gene	N/A	NP_001015048.1	A0A024R6M6
	COA8	NM_001370595.2	MANE Select	c.-151_-150insCCG		upstream_gene	N/A	NP_001357524.1	A0A6Q8JUI0
	COA8	NM_001302653.2		c.-151_-150insCCG		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+868insCCG		intron	N/A	ENSP00000450786.1	G3V2P7
	BAG5	ENST00000299204.6	TSL:1 MANE Select	c.-265_-264insCGG		upstream_gene	N/A	ENSP00000299204.4	Q9UL15-1
	COA8	ENST00000409074.8	TSL:1 MANE Select	c.-151_-150insCCG		upstream_gene	N/A	ENSP00000386485.3	A0A6Q8JUI0

Frequencies

GnomAD3 genomes AF: 0.244 AC: 36875 AN: 151206 Hom.: 4954 Cov.: 26

Gnomad AFR AF: 0.144

Gnomad AMI AF: 0.305

Gnomad AMR AF: 0.272

Gnomad ASJ AF: 0.248

Gnomad EAS AF: 0.347

Gnomad SAS AF: 0.136

Gnomad FIN AF: 0.322

Gnomad MID AF: 0.239

Gnomad NFE AF: 0.286

Gnomad OTH AF: 0.240

GnomAD4 exome AF: 0.262 AC: 261079 AN: 995548 Hom.: 36004 Cov.: 15 AF XY: 0.260 AC XY: 124072 AN XY: 477390

African (AFR) AF: 0.126 AC: 2509 AN: 19910

American (AMR) AF: 0.288 AC: 2140 AN: 7428

Ashkenazi Jewish (ASJ) AF: 0.229 AC: 3045 AN: 13300

East Asian (EAS) AF: 0.288 AC: 6799 AN: 23576

South Asian (SAS) AF: 0.106 AC: 3040 AN: 28752

European-Finnish (FIN) AF: 0.297 AC: 7059 AN: 23780

Middle Eastern (MID) AF: 0.180 AC: 499 AN: 2776

European-Non Finnish (NFE) AF: 0.271 AC: 225917 AN: 835144

Other (OTH) AF: 0.246 AC: 10071 AN: 40882

GnomAD4 genome AF: 0.244 AC: 36899 AN: 151314 Hom.: 4970 Cov.: 26 AF XY: 0.244 AC XY: 18037 AN XY: 73958

African (AFR) AF: 0.143 AC: 5916 AN: 41260

American (AMR) AF: 0.273 AC: 4153 AN: 15230

Ashkenazi Jewish (ASJ) AF: 0.248 AC: 857 AN: 3462

East Asian (EAS) AF: 0.346 AC: 1772 AN: 5122

South Asian (SAS) AF: 0.138 AC: 665 AN: 4826

European-Finnish (FIN) AF: 0.322 AC: 3332 AN: 10362

Middle Eastern (MID) AF: 0.236 AC: 69 AN: 292

European-Non Finnish (NFE) AF: 0.286 AC: 19350 AN: 67748

Other (OTH) AF: 0.241 AC: 507 AN: 2102

Alfa AF: 0.262 Hom.: 568

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, single submitter

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

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		-0.48
Mutation Taster		=100/0	polymorphism (auto)

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;