rs750069192

Variant names:

• chr9-114092426-G-A
• rs750069192
• NM_001388308.1:c.1723C>T

Your query was ambiguous. Multiple possible variants found:

• chr9-114092426-G-A
• chr9-114092426-G-C
• chr9-114092426-G-T

Variant summary

Our verdict is Pathogenic. The variant received 12 ACMG points: 12P and 0B. PVS1 PM2 PP5_Moderate

The NM_001388308.1(KIF12):​c.1723C>T​(p.Arg575*) variant causes a stop gained change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000753 in 1,461,176 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★). Variant results in nonsense mediated mRNA decay.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000075 (0 hom.)
• Consequence: KIF12 NM_001388308.1 stop_gained
• Clinical Significance: Likely pathogenic criteria provided, single submitter P:1
• Conservation: PhyloP100: 0.740
• Publications: 0 publications found

Genes affected

KIF12 (HGNC:21495): (kinesin family member 12) This gene encodes a member of the kinesin superfamily of microtubule-associated molecular motors with functions related to the microtubule cytosekelton. Members of this superfamily play important roles in intracellular transport and cell division. A similar protein in mouse functions in the beta cell antioxidant signaling cascade, acting as a scaffold for the transcription factor specificity protein 1 (Sp1). Mice that lack this gene exhibit beta cell oxidative stress resulting in hypoinsulinemic glucose intolerance. [provided by RefSeq, Jul 2016]

KIF12 Gene-Disease associations (from GenCC):

• cholestasis

  Inheritance: AR Classification: DEFINITIVE Submitted by: King Faisal Specialist Hospital and Research Center
• cholestasis, progressive familial intrahepatic, 8

  Inheritance: AR Classification: STRONG, MODERATE Submitted by: Ambry Genetics, Labcorp Genetics (formerly Invitae)

ACMG classification

Our verdict: Pathogenic. The variant received 12 ACMG points.

• PVS1: Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 9-114092426-G-A is Pathogenic according to our data. Variant chr9-114092426-G-A is described in ClinVar as Likely_pathogenic. ClinVar VariationId is 3064812.Status of the report is criteria_provided_single_submitter, 1 stars.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001388308.1. 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
	KIF12	NM_001388308.1	MANE Select	c.1723C>T	p.Arg575*	stop_gained	Exon 18 of 19	NP_001375237.1	A0A1W2PPS5
	KIF12	NM_138424.2		c.1309C>T	p.Arg437*	stop_gained	Exon 15 of 16	NP_612433.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	KIF12	ENST00000640217.2	TSL:5 MANE Select	c.1723C>T	p.Arg575*	stop_gained	Exon 18 of 19	ENSP00000491702.1	A0A1W2PPS5
	KIF12	ENST00000640553.1	TSL:1	n.1547C>T		non_coding_transcript_exon	Exon 15 of 16
	KIF12	ENST00000905877.1		c.1618C>T	p.Arg540*	stop_gained	Exon 17 of 18	ENSP00000575936.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD2 exomes AF: 0.00000399 AC: 1 AN: 250664 AF XY: 0.00000738

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000753 AC: 11 AN: 1461176 Hom.: 0 Cov.: 32 AF XY: 0.00000825 AC XY: 6 AN XY: 726866

African (AFR) AF: 0.00 AC: 0 AN: 33456

American (AMR) AF: 0.00 AC: 0 AN: 44626

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26078

East Asian (EAS) AF: 0.00 AC: 0 AN: 39690

South Asian (SAS) AF: 0.0000348 AC: 3 AN: 86184

European-Finnish (FIN) AF: 0.0000188 AC: 1 AN: 53276

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5762

European-Non Finnish (NFE) AF: 0.00000540 AC: 6 AN: 1111732

Other (OTH) AF: 0.0000166 AC: 1 AN: 60372

GnomAD4 genome Cov.: 32

ClinVar

ClinVar submissions

Significance: Likely pathogenic

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
1	-	-	Cholestasis, progressive familial intrahepatic, 8 (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.27	D
BayesDel_noAF	Pathogenic	0.25
CADD	Pathogenic	36
DANN	Uncertain	0.97
Eigen	Benign	-0.00052
Eigen_PC	Benign	-0.34
FATHMM_MKL	Benign	0.093	N
PhyloP100		0.74
Vest4		0.28
GERP RS		-1.5
PromoterAI		0.0045	Neutral
Mutation Taster		=88/112	disease causing (fs/PTC)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs750069192; hg19: chr9-116854706; COSMIC: COSV65117771; COSMIC: COSV65117771;