9-114092434-G-C

Variant names:

• chr9-114092434-G-C
• rs147277754
• NM_001388308.1:c.1715C>G

Variant summary

Our verdict is Benign. Variant got -13 ACMG points: 0P and 13B. BP4_Strong BP6 BS1 BS2

The NM_001388308.1(KIF12):​c.1715C>G​(p.Thr572Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00246 in 1,613,720 control chromosomes in the GnomAD database, including 16 homozygotes. In-silico tool predicts a benign outcome for this variant. 16/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.0014 (1 hom., cov: 32)
  • Exomes 𝑓: 0.0026 (15 hom.)
• Consequence: KIF12 NM_001388308.1 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:1
• Conservation: PhyloP100: 0.0300

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 Benign. Variant got -13 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0039387345).
• BP6: Variant 9-114092434-G-C is Benign according to our data. Variant chr9-114092434-G-C is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 2061783.We mark this variant Likely_benign, oryginal submissions are: {Benign=1, Uncertain_significance=1}.
• BS1: Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.00137 (208/152264) while in subpopulation NFE AF= 0.00268 (182/68002). AF 95% confidence interval is 0.00236. There are 1 homozygotes in gnomad4. There are 91 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.
• BS2: High Homozygotes in GnomAdExome4 at 15 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
KIF12	NM_001388308.1	c.1715C>G	p.Thr572Ser	missense_variant	Exon 18 of 19	ENST00000640217.2	NP_001375237.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
KIF12	ENST00000640217.2	c.1715C>G	p.Thr572Ser	missense_variant	Exon 18 of 19	5	NM_001388308.1	ENSP00000491702.1

Frequencies

GnomAD3 genomes AF: 0.00137 AC: 208 AN: 152146 Hom.: 1 Cov.: 32

Gnomad AFR AF: 0.000579

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000131

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: 0.00268

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.00137 AC: 344 AN: 250958 Hom.: 1 AF XY: 0.00133 AC XY: 181 AN XY: 135678

Gnomad AFR exome AF: 0.000369

Gnomad AMR exome AF: 0.0000290

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.0000924

Gnomad NFE exome AF: 0.00288

Gnomad OTH exome AF: 0.00131

GnomAD4 exome AF: 0.00257 AC: 3755 AN: 1461456 Hom.: 15 Cov.: 32 AF XY: 0.00247 AC XY: 1798 AN XY: 727042

Gnomad4 AFR exome AF: 0.000299

Gnomad4 AMR exome AF: 0.0000895

Gnomad4 ASJ exome AF: 0.0000383

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.000244

Gnomad4 NFE exome AF: 0.00329

Gnomad4 OTH exome AF: 0.00114

GnomAD4 genome AF: 0.00137 AC: 208 AN: 152264 Hom.: 1 Cov.: 32 AF XY: 0.00122 AC XY: 91 AN XY: 74444

Gnomad4 AFR AF: 0.000577

Gnomad4 AMR AF: 0.000131

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.00268

Gnomad4 OTH AF: 0.00

Alfa AF: 0.00235 Hom.: 1

Bravo AF: 0.00130

TwinsUK AF: 0.00324 AC: 12

ALSPAC AF: 0.00285 AC: 11

ESP6500AA AF: 0.000454 AC: 2

ESP6500EA AF: 0.00174 AC: 15

ExAC AF: 0.00129 AC: 157

EpiCase AF: 0.00229

EpiControl AF: 0.00261

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1 Benign:1

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not provided Uncertain:1 Benign:1

Feb 17, 2023

Mayo Clinic Laboratories, Mayo Clinic

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

BP4 -

Nov 12, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.077
BayesDel_addAF	Benign	-0.54	T
BayesDel_noAF	Benign	-0.54
CADD	Benign	12
DANN	Benign	0.92
DEOGEN2	Benign	0.0064	.;.;T
Eigen	Benign	-0.93
Eigen_PC	Benign	-0.93
FATHMM_MKL	Benign	0.030	N
LIST_S2	Benign	0.47	T;T;T
M_CAP	Benign	0.023	T
MetaRNN	Benign	0.0039	T;T;T
MetaSVM	Benign	-0.99	T
MutationAssessor	Benign	1.4	.;.;L
PrimateAI	Benign	0.38	T
PROVEAN	Benign	-0.35	.;N;.
REVEL	Benign	0.080
Sift	Benign	0.10	.;T;.
Sift4G	Benign	0.37	.;T;.
Polyphen		0.18	.;.;B
Vest4		0.20
MutPred		0.053		.;.;Gain of MoRF binding (P = 0.1148);
MVP		0.37
MPC		0.15
ClinPred		0.0021	T
GERP RS		-2.2
Varity_R		0.040
gMVP		0.12

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

Publications

LitVar

Other links and lift over

dbSNP: rs147277754; hg19: chr9-116854714;