8-144466436-C-A

Variant names:

• chr8-144466436-C-A
• rs753498379
• NM_001369769.2:c.17C>A

Variant summary

Our verdict is Uncertain significance. The variant received 2 ACMG points: 2P and 0B. PM2

The NM_001369769.2(KIFC2):​c.17C>A​(p.Ser6*) variant causes a stop gained change. The variant allele was found at a frequency of 0.000000828 in 1,207,292 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: not found (cov: 30)
  • Exomes 𝑓: 8.3e-7 (0 hom.)
• Consequence: KIFC2 NM_001369769.2 stop_gained
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 5.04
• Publications: 0 publications found

Genes affected

KIFC2 (HGNC:29530): (kinesin family member C2) Predicted to enable microtubule binding activity and microtubule motor activity. Predicted to be involved in microtubule-based movement and mitotic spindle assembly. Predicted to be located in cytoplasm. Predicted to be part of kinesin complex. Predicted to be active in microtubule cytoskeleton and nucleus. [provided by Alliance of Genome Resources, Apr 2022]

TMEM276 (HGNC:56235): (transmembrane protein 276)

ACMG classification

Our verdict: Uncertain_significance. The variant received 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001369769.2. 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
	KIFC2	NM_001369769.2	MANE Select	c.17C>A	p.Ser6*	stop_gained	Exon 1 of 18	NP_001356698.1	A0A2R8YEU8
	KIFC2	NM_145754.5		c.17C>A	p.Ser6*	stop_gained	Exon 1 of 17	NP_665697.1	Q96AC6-1
	TMEM276	NM_001408061.1		c.-348G>T		5_prime_UTR	Exon 1 of 3	NP_001394990.1	P0DTL5

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	KIFC2	ENST00000645548.2	MANE Select	c.17C>A	p.Ser6*	stop_gained	Exon 1 of 18	ENSP00000494595.1	A0A2R8YEU8
	KIFC2	ENST00000301332.3	TSL:1	c.17C>A	p.Ser6*	stop_gained	Exon 1 of 17	ENSP00000301332.2	Q96AC6-1
	KIFC2	ENST00000880943.1		c.17C>A	p.Ser6*	stop_gained	Exon 1 of 19	ENSP00000551002.1

Frequencies

GnomAD3 genomes Cov.: 30

GnomAD4 exome AF: 8.28e-7 AC: 1 AN: 1207292 Hom.: 0 Cov.: 28 AF XY: 0.00000167 AC XY: 1 AN XY: 597730

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.00 AC: 0 AN: 24062

American (AMR) AF: 0.00 AC: 0 AN: 22984

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 18028

East Asian (EAS) AF: 0.0000416 AC: 1 AN: 24036

South Asian (SAS) AF: 0.00 AC: 0 AN: 56204

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 37684

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 4626

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 973778

Other (OTH) AF: 0.00 AC: 0 AN: 45890

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome Cov.: 30

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.56	D
BayesDel_noAF	Pathogenic	0.57
CADD	Pathogenic	43
DANN	Uncertain	0.99
Eigen	Uncertain	0.65
Eigen_PC	Uncertain	0.45
FATHMM_MKL	Uncertain	0.91	D
PhyloP100		5.0
Vest4		0.096
GERP RS		3.8
PromoterAI		-0.010	Neutral
Mutation Taster		=44/156	disease causing (fs/PTC)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.12		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: rs753498379; hg19: chr8-145691819; COSMIC: COSV100023774; COSMIC: COSV100023774;