14-103699590-T-C

Variant names:

• chr14-103699590-T-C
• rs1799796
• NM_001394837.1:c.1849-1065T>C

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_001394837.1(KLC1):​c.1849-1065T>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.312 in 1,612,304 control chromosomes in the GnomAD database, including 81,219 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as risk factor (no stars).

• Frequency:
  • Genomes: 𝑓 0.28 (6740 hom., cov: 31)
  • Exomes 𝑓: 0.31 (74479 hom.)
• Consequence: KLC1 NM_001394837.1 intron
• Clinical Significance: risk factor no assertion criteria provided O:1
• Conservation: PhyloP100: -5.33
• Publications: 74 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]

XRCC3 (HGNC:12830): (X-ray repair cross complementing 3) This gene encodes a member of the RecA/Rad51-related protein family that participates in homologous recombination to maintain chromosome stability and repair DNA damage. This gene functionally complements Chinese hamster irs1SF, a repair-deficient mutant that exhibits hypersensitivity to a number of different DNA-damaging agents and is chromosomally unstable. A rare microsatellite polymorphism in this gene is associated with cancer in patients of varying radiosensitivity. Alternatively spliced transcript variants encoding the same protein have been identified. [provided by RefSeq, Jul 2008]

ACMG classification

Our verdict: Benign. The variant received -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.95).
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.344 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
KLC1	NM_001394837.1	c.1849-1065T>C		intron_variant	Intron 15 of 16	ENST00000334553.11	NP_001381766.1
XRCC3	NM_005432.4	c.562-14A>G		intron_variant	Intron 7 of 9	ENST00000555055.6	NP_005423.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
KLC1	ENST00000334553.11	c.1849-1065T>C		intron_variant	Intron 15 of 16	5	NM_001394837.1	ENSP00000334523.6
XRCC3	ENST00000555055.6	c.562-14A>G		intron_variant	Intron 7 of 9	1	NM_005432.4	ENSP00000452598.1

Frequencies

GnomAD3 genomes AF: 0.281 AC: 42601 AN: 151724 Hom.: 6727 Cov.: 31

Gnomad AFR AF: 0.158

Gnomad AMI AF: 0.311

Gnomad AMR AF: 0.289

Gnomad ASJ AF: 0.217

Gnomad EAS AF: 0.358

Gnomad SAS AF: 0.200

Gnomad FIN AF: 0.434

Gnomad MID AF: 0.225

Gnomad NFE AF: 0.333

Gnomad OTH AF: 0.261

GnomAD2 exomes AF: 0.308 AC: 76441 AN: 248434 AF XY: 0.301

Gnomad AFR exome AF: 0.156

Gnomad AMR exome AF: 0.342

Gnomad ASJ exome AF: 0.218

Gnomad EAS exome AF: 0.363

Gnomad FIN exome AF: 0.425

Gnomad NFE exome AF: 0.325

Gnomad OTH exome AF: 0.301

GnomAD4 exome AF: 0.315 AC: 459606 AN: 1460462 Hom.: 74479 Cov.: 36 AF XY: 0.310 AC XY: 225490 AN XY: 726574

African (AFR) AF: 0.146 AC: 4871 AN: 33476

American (AMR) AF: 0.336 AC: 14997 AN: 44682

Ashkenazi Jewish (ASJ) AF: 0.213 AC: 5552 AN: 26126

East Asian (EAS) AF: 0.340 AC: 13491 AN: 39686

South Asian (SAS) AF: 0.204 AC: 17617 AN: 86226

European-Finnish (FIN) AF: 0.421 AC: 22113 AN: 52558

Middle Eastern (MID) AF: 0.192 AC: 1107 AN: 5768

European-Non Finnish (NFE) AF: 0.326 AC: 362187 AN: 1111574

Other (OTH) AF: 0.293 AC: 17671 AN: 60366

GnomAD4 genome AF: 0.281 AC: 42630 AN: 151842 Hom.: 6740 Cov.: 31 AF XY: 0.282 AC XY: 20935 AN XY: 74212

African (AFR) AF: 0.158 AC: 6523 AN: 41378

American (AMR) AF: 0.290 AC: 4427 AN: 15280

Ashkenazi Jewish (ASJ) AF: 0.217 AC: 753 AN: 3470

East Asian (EAS) AF: 0.358 AC: 1839 AN: 5138

South Asian (SAS) AF: 0.201 AC: 967 AN: 4804

European-Finnish (FIN) AF: 0.434 AC: 4581 AN: 10564

Middle Eastern (MID) AF: 0.231 AC: 68 AN: 294

European-Non Finnish (NFE) AF: 0.333 AC: 22635 AN: 67894

Other (OTH) AF: 0.263 AC: 554 AN: 2110

Alfa AF: 0.300 Hom.: 3547

Bravo AF: 0.265

Asia WGS AF: 0.262 AC: 910 AN: 3478

ClinVar

Significance: risk factor

Submissions summary: Other:1

Revision: no assertion criteria provided

Submissions by phenotype

Breast cancer, susceptibility to Other:1

Jun 01, 2002

OMIM

Significance: risk factor

Review Status: no assertion criteria provided

Collection Method: literature only

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.95
CADD	Benign	0.035
DANN	Benign	0.37
PhyloP100		-5.3
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Mutation Taster		=100/0	polymorphism (auto)

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

Other links and lift over

dbSNP: rs1799796; hg19: chr14-104165927; COSMIC: COSV57975256; COSMIC: COSV57975256;