14-103562952-G-T

Variant summary

Our verdict is Benign. Variant got -14 ACMG points: 0P and 14B. BP4_Strong BP6_Moderate BS1 BS2

The ENST00000557172.5(KLC1):c.-2+968G>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00599 in 1,440,974 control chromosomes in the GnomAD database, including 49 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

• Frequency:
  • Genomes: 𝑓 0.0054 (1 hom., cov: 34)
  • Exomes 𝑓: 0.0061 (48 hom.)
• Consequence: KLC1 ENST00000557172.5 intron
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 0.185

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]

ACMG classification

Verdict is Benign. Variant got -14 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.78).
• BP6: Variant 14-103562952-G-T is Benign according to our data. Variant chr14-103562952-G-T is described in ClinVar as [Benign]. Clinvar id is 380166.Status of the report is criteria_provided_single_submitter, 1 stars.
• BS1: Variant frequency is greater than expected in population sas. gnomad4_exome allele frequency = 0.00606 (7816/1288718) while in subpopulation SAS AF= 0.0177 (1177/66390). AF 95% confidence interval is 0.0169. There are 48 homozygotes in gnomad4_exome. There are 4022 alleles in male gnomad4_exome subpopulation. Median coverage is 32. This position pass quality control queck.
• BS2: High AC in GnomAd at 820 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
COA8	NM_001370595.2			upstream_gene_variant		ENST00000409074.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
COA8	ENST00000409074.8			upstream_gene_variant		1	NM_001370595.2	P1

Frequencies

GnomAD3 genomes AF: 0.00539 AC: 820 AN: 152144 Hom.: 1 Cov.: 34

Gnomad AFR AF: 0.000869

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00530

Gnomad ASJ AF: 0.0187

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.0149

Gnomad FIN AF: 0.0117

Gnomad MID AF: 0.00955

Gnomad NFE AF: 0.00632

Gnomad OTH AF: 0.00431

GnomAD3 exomes AF: 0.00832 AC: 477 AN: 57338 Hom.: 10 AF XY: 0.00854 AC XY: 279 AN XY: 32680

Gnomad AFR exome AF: 0.000433

Gnomad AMR exome AF: 0.00327

Gnomad ASJ exome AF: 0.0192

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.0177

Gnomad FIN exome AF: 0.0121

Gnomad NFE exome AF: 0.00728

Gnomad OTH exome AF: 0.0124

GnomAD4 exome AF: 0.00606 AC: 7816 AN: 1288718 Hom.: 48 Cov.: 32 AF XY: 0.00638 AC XY: 4022 AN XY: 630028

Gnomad4 AFR exome AF: 0.000853

Gnomad4 AMR exome AF: 0.00374

Gnomad4 ASJ exome AF: 0.0175

Gnomad4 EAS exome AF: 0.0000320

Gnomad4 SAS exome AF: 0.0177

Gnomad4 FIN exome AF: 0.0134

Gnomad4 NFE exome AF: 0.00516

Gnomad4 OTH exome AF: 0.00755

GnomAD4 genome AF: 0.00539 AC: 821 AN: 152256 Hom.: 1 Cov.: 34 AF XY: 0.00545 AC XY: 406 AN XY: 74436

Gnomad4 AFR AF: 0.000866

Gnomad4 AMR AF: 0.00529

Gnomad4 ASJ AF: 0.0187

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.0151

Gnomad4 FIN AF: 0.0117

Gnomad4 NFE AF: 0.00632

Gnomad4 OTH AF: 0.00426

Alfa AF: 0.00818 Hom.: 6

Bravo AF: 0.00426

Asia WGS AF: 0.00722 AC: 25 AN: 3474

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Benign:1

Benign, criteria provided, single submitter

clinical testing

GeneDx

Nov 14, 2016

This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.78
Cadd	Benign	9.5
Dann	Benign	0.84

Splicing

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

Publications

LitVar

Other links and lift over

dbSNP: rs185675160; hg19: chr14-104029289;