14-103562909-G-A

Variant names:

• chr14-103562909-G-A
• rs2274269
• ENST00000557172.5:c.-2+925G>A

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The ENST00000557172.5(KLC1):​c.-2+925G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.331 in 1,350,200 control chromosomes in the GnomAD database, including 76,159 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.29 (6902 hom., cov: 34)
  • Exomes 𝑓: 0.34 (69257 hom.)
• Consequence: KLC1 ENST00000557172.5 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -0.937
• Publications: 11 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]

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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.75).
• BP6: Variant 14-103562909-G-A is Benign according to our data. Variant chr14-103562909-G-A is described in ClinVar as Benign. ClinVar VariationId is 1270467.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.347 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
	COA8	NM_001370595.2	MANE Select	c.-93G>A		upstream_gene	N/A	NP_001357524.1	A0A6Q8JUI0
	COA8	NM_001302653.2		c.-93G>A		upstream_gene	N/A	NP_001289582.2	G3V4L6
	COA8	NM_001302654.2		c.-93G>A		upstream_gene	N/A	NP_001289583.2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	KLC1	ENST00000557172.5	TSL:4	c.-2+925G>A		intron	N/A	ENSP00000450786.1	G3V2P7
	COA8	ENST00000409074.8	TSL:1 MANE Select	c.-93G>A		upstream_gene	N/A	ENSP00000386485.3	A0A6Q8JUI0
	ENSG00000256500	ENST00000472726.3	TSL:2	c.-93G>A		upstream_gene	N/A	ENSP00000439065.2	E7EVH7

Frequencies

GnomAD3 genomes AF: 0.295 AC: 44729 AN: 151870 Hom.: 6900 Cov.: 34

Gnomad AFR AF: 0.253

Gnomad AMI AF: 0.310

Gnomad AMR AF: 0.247

Gnomad ASJ AF: 0.354

Gnomad EAS AF: 0.0795

Gnomad SAS AF: 0.224

Gnomad FIN AF: 0.276

Gnomad MID AF: 0.379

Gnomad NFE AF: 0.351

Gnomad OTH AF: 0.311

GnomAD4 exome AF: 0.336 AC: 402379 AN: 1198220 Hom.: 69257 Cov.: 30 AF XY: 0.335 AC XY: 193352 AN XY: 577804

African (AFR) AF: 0.259 AC: 6056 AN: 23376

American (AMR) AF: 0.218 AC: 2018 AN: 9260

Ashkenazi Jewish (ASJ) AF: 0.346 AC: 5741 AN: 16600

East Asian (EAS) AF: 0.119 AC: 3203 AN: 27018

South Asian (SAS) AF: 0.243 AC: 12502 AN: 51354

European-Finnish (FIN) AF: 0.295 AC: 8464 AN: 28718

Middle Eastern (MID) AF: 0.373 AC: 1253 AN: 3358

European-Non Finnish (NFE) AF: 0.351 AC: 347553 AN: 989226

Other (OTH) AF: 0.316 AC: 15589 AN: 49310

GnomAD4 genome AF: 0.294 AC: 44732 AN: 151980 Hom.: 6902 Cov.: 34 AF XY: 0.288 AC XY: 21374 AN XY: 74284

African (AFR) AF: 0.252 AC: 10481 AN: 41512

American (AMR) AF: 0.247 AC: 3775 AN: 15278

Ashkenazi Jewish (ASJ) AF: 0.354 AC: 1229 AN: 3470

East Asian (EAS) AF: 0.0795 AC: 411 AN: 5170

South Asian (SAS) AF: 0.224 AC: 1084 AN: 4832

European-Finnish (FIN) AF: 0.276 AC: 2901 AN: 10510

Middle Eastern (MID) AF: 0.380 AC: 111 AN: 292

European-Non Finnish (NFE) AF: 0.351 AC: 23809 AN: 67894

Other (OTH) AF: 0.307 AC: 649 AN: 2112

Alfa AF: 0.313 Hom.: 941

Bravo AF: 0.290

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	2	not provided (2)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.75
CADD	Benign	3.4
DANN	Benign	0.94
PhyloP100		-0.94
PromoterAI		-0.013	Neutral
Mutation Taster		=100/0	polymorphism

Splicing

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

Other links and lift over

dbSNP: rs2274269; hg19: chr14-104029246; COSMIC: COSV99914570;