9-114091903-A-C

Variant summary

Our verdict is Likely benign. Variant got -3 ACMG points: 2P and 5B. PM2 BP4_Strong BP6

The NM_001388308.1(KIF12):c.1914T>G(p.Ser638Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000813 in 1,611,496 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Synonymous variant affecting the same amino acid position (i.e. S638S) has been classified as Benign.

• Frequency:
  • Genomes: 𝑓 0.00047 (1 hom., cov: 32)
  • Exomes 𝑓: 0.000040 (0 hom.)
• Consequence: KIF12 NM_001388308.1 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:1
• Conservation: PhyloP100: -1.97

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]

ACMG classification

Verdict is Likely_benign. Variant got -3 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.014159083).
• BP6: Variant 9-114091903-A-C is Benign according to our data. Variant chr9-114091903-A-C is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 2695099.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=1, Uncertain_significance=1}.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
KIF12	NM_001388308.1	c.1914T>G	p.Ser638Arg	missense_variant	19/19	ENST00000640217.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
KIF12	ENST00000640217.2	c.1914T>G	p.Ser638Arg	missense_variant	19/19	5	NM_001388308.1	P1

Frequencies

GnomAD3 genomes AF: 0.000474 AC: 72 AN: 151998 Hom.: 1 Cov.: 32

Gnomad AFR AF: 0.00171

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000147

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.0000928 AC: 23 AN: 247856 Hom.: 0 AF XY: 0.0000595 AC XY: 8 AN XY: 134532

Gnomad AFR exome AF: 0.00124

Gnomad AMR exome AF: 0.0000580

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00000903

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000404 AC: 59 AN: 1459498 Hom.: 0 Cov.: 31 AF XY: 0.0000303 AC XY: 22 AN XY: 725734

Gnomad4 AFR exome AF: 0.00152

Gnomad4 AMR exome AF: 0.0000672

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 9.00e-7

Gnomad4 OTH exome AF: 0.0000664

GnomAD4 genome AF: 0.000474 AC: 72 AN: 151998 Hom.: 1 Cov.: 32 AF XY: 0.000431 AC XY: 32 AN XY: 74226

Gnomad4 AFR AF: 0.00171

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000147

Gnomad4 OTH AF: 0.00

Bravo AF: 0.000552

ExAC AF: 0.000115 AC: 14

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1 Benign:1

Revision: criteria provided, conflicting classifications

Submissions by phenotype

Inborn genetic diseases Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Oct 12, 2021

The c.1500T>G (p.S500R) alteration is located in exon 16 (coding exon 14) of the KIF12 gene. This alteration results from a T to G substitution at nucleotide position 1500, causing the serine (S) at amino acid position 500 to be replaced by an arginine (R). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

not provided Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Invitae

Oct 16, 2023

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.12
BayesDel_addAF	Benign	-0.50	T
BayesDel_noAF	Benign	-0.50
Cadd	Benign	0.089
Dann	Benign	0.93
Eigen	Benign	-1.6
Eigen_PC	Benign	-1.7
FATHMM_MKL	Benign	0.0095	N
LIST_S2	Benign	0.51	T;T;T
M_CAP	Benign	0.015	T
MetaRNN	Benign	0.014	T;T;T
MetaSVM	Benign	-0.91	T
MutationTaster	Benign	1.0	N;N
PrimateAI	Benign	0.35	T
Polyphen		0.0	.;.;B
Vest4		0.11
MutPred		0.086		.;.;Gain of MoRF binding (P = 0.0153);
MVP		0.17
MPC		0.19
ClinPred		0.018	T
GERP RS		-7.6
Varity_R		0.071
gMVP		0.21

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

Publications

LitVar

Other links and lift over

dbSNP: rs117751044; hg19: chr9-116854183;