rs116823950

Variant names:

• chr15-89642262-C-G
• rs116823950
• NM_198525.3:c.2335G>C

Your query was ambiguous. Multiple possible variants found:

• chr15-89642262-C-G
• chr15-89642262-C-T
• chr15-89642262-C-A

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The NM_198525.3(KIF7):​c.2335G>C​(p.Glu779Gln) variant causes a missense change. The variant allele was found at a frequency of 0.000458 in 1,610,384 control chromosomes in the GnomAD database, including 2 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. E779K) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.0025 (2 hom., cov: 31)
  • Exomes 𝑓: 0.00024 (0 hom.)
• Consequence: KIF7 NM_198525.3 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:5
• Conservation: PhyloP100: 4.05
• Publications: 4 publications found

Genes affected

KIF7 (HGNC:30497): (kinesin family member 7) This gene encodes a cilia-associated protein belonging to the kinesin family. This protein plays a role in the sonic hedgehog (SHH) signaling pathway through the regulation of GLI transcription factors. It functions as a negative regulator of the SHH pathway by preventing inappropriate activation of GLI2 in the absence of ligand, and as a positive regulator by preventing the processing of GLI3 into its repressor form. Mutations in this gene have been associated with various ciliopathies. [provided by RefSeq, Oct 2011]

KIF7 Gene-Disease associations (from GenCC):

• acrocallosal syndrome

  Inheritance: AR Classification: DEFINITIVE, STRONG, MODERATE, SUPPORTIVE Submitted by: Ambry Genetics, G2P, Labcorp Genetics (formerly Invitae), Orphanet
• neurodevelopmental disorder

  Inheritance: AR Classification: DEFINITIVE Submitted by: G2P
• hydrolethalus syndrome 2

  Inheritance: AR Classification: STRONG, MODERATE Submitted by: Genomics England PanelApp, Labcorp Genetics (formerly Invitae)
• hydrolethalus syndrome

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet
• multiple epiphyseal dysplasia, Al-Gazali type

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet
• orofaciodigital syndrome type 6

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Benign. The variant received -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.008992642).
• BP6: Variant 15-89642262-C-G is Benign according to our data. Variant chr15-89642262-C-G is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 193948.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.00253 (386/152290) while in subpopulation AFR AF = 0.00868 (361/41576). AF 95% confidence interval is 0.00794. There are 2 homozygotes in GnomAd4. There are 171 alleles in the male GnomAd4 subpopulation. Median coverage is 31. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 2 AR gene

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_198525.3. 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
	KIF7	NM_198525.3	MANE Select	c.2335G>C	p.Glu779Gln	missense	Exon 11 of 19	NP_940927.2	Q2M1P5

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	KIF7	ENST00000394412.8	TSL:5 MANE Select	c.2335G>C	p.Glu779Gln	missense	Exon 11 of 19	ENSP00000377934.3	Q2M1P5
	KIF7	ENST00000696512.1		c.2458G>C	p.Glu820Gln	missense	Exon 11 of 19	ENSP00000512678.1	A0A8Q3SIQ8
	KIF7	ENST00000946200.1		c.2347G>C	p.Glu783Gln	missense	Exon 11 of 19	ENSP00000616259.1

Frequencies

GnomAD3 genomes AF: 0.00254 AC: 386 AN: 152172 Hom.: 2 Cov.: 31

Gnomad AFR AF: 0.00871

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00111

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: 0.00335

GnomAD2 exomes AF: 0.000712 AC: 175 AN: 245690 AF XY: 0.000479

Gnomad AFR exome AF: 0.00986

Gnomad AMR exome AF: 0.000494

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: 0.000331

GnomAD4 exome AF: 0.000241 AC: 351 AN: 1458094 Hom.: 0 Cov.: 32 AF XY: 0.000198 AC XY: 144 AN XY: 725556

African (AFR) AF: 0.00879 AC: 294 AN: 33446

American (AMR) AF: 0.000492 AC: 22 AN: 44704

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26110

East Asian (EAS) AF: 0.00 AC: 0 AN: 39692

South Asian (SAS) AF: 0.0000232 AC: 2 AN: 86188

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 50768

Middle Eastern (MID) AF: 0.000192 AC: 1 AN: 5196

European-Non Finnish (NFE) AF: 0.00000180 AC: 2 AN: 1111722

Other (OTH) AF: 0.000498 AC: 30 AN: 60268

GnomAD4 genome AF: 0.00253 AC: 386 AN: 152290 Hom.: 2 Cov.: 31 AF XY: 0.00230 AC XY: 171 AN XY: 74466

African (AFR) AF: 0.00868 AC: 361 AN: 41576

American (AMR) AF: 0.00111 AC: 17 AN: 15304

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5150

South Asian (SAS) AF: 0.00 AC: 0 AN: 4824

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10618

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.0000147 AC: 1 AN: 68030

Other (OTH) AF: 0.00331 AC: 7 AN: 2112

Alfa AF: 0.000155 Hom.: 0

Bravo AF: 0.00322

ESP6500AA AF: 0.00933 AC: 41

ESP6500EA AF: 0.00 AC: 0

ExAC AF: 0.000874 AC: 106

Asia WGS AF: 0.000577 AC: 2 AN: 3478

ClinVar

ClinVar submissions

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	2	not provided (2)
-	-	2	not specified (2)
-	-	1	Acrocallosal syndrome (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.11
BayesDel_addAF	Benign	-0.49	T
BayesDel_noAF	Benign	-0.47
CADD	Benign	22
DANN	Uncertain	1.0
DEOGEN2	Benign	0.13	T
Eigen	Uncertain	0.41
Eigen_PC	Uncertain	0.38
FATHMM_MKL	Uncertain	0.92	D
LIST_S2	Benign	0.73	T
MetaRNN	Benign	0.0090	T
MetaSVM	Benign	-0.84	T
MutationAssessor	Uncertain	2.4	M
PhyloP100		4.1
PrimateAI	Uncertain	0.52	T
PROVEAN	Benign	-1.4	N
REVEL	Benign	0.16
Sift	Benign	0.19	T
Sift4G	Benign	0.31	T
Polyphen		1.0	D
Vest4		0.42
MVP		0.55
MPC		0.038
ClinPred		0.015	T
GERP RS		4.9
Varity_R		0.24
gMVP		0.21
Mutation Taster		=89/11	polymorphism

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: rs116823950; hg19: chr15-90185493;