rs386834053

Variant names:

• chr17-58210980-C-G
• rs386834053
• NM_017777.4:c.958G>C

Your query was ambiguous. Multiple possible variants found:

• chr17-58210980-C-G
• chr17-58210980-C-T

Variant summary

Our verdict is Likely pathogenic. The variant received 8 ACMG points: 8P and 0B. PM2 PM5 PP3_Strong

The NM_017777.4(MKS1):​c.958G>C​(p.Val320Leu) variant causes a missense, splice region change. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 3/3 splice prediction tools predicting alterations to normal splicing. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. V320I) has been classified as Likely pathogenic.

• Frequency: Genomes: not found (cov: 32)
• Consequence: MKS1 NM_017777.4 missense, splice_region
• Scores: Splicing: ADA: 1.000
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 4.66
• Publications: 0 publications found

Genes affected

MKS1 (HGNC:7121): (MKS transition zone complex subunit 1) The protein encoded by this gene localizes to the basal body and is required for formation of the primary cilium in ciliated epithelial cells. Mutations in this gene result in Meckel syndrome type 1 and in Bardet-Biedl syndrome type 13. Multiple transcript variants encoding different isoforms have been found for this gene. [provided by RefSeq, Sep 2009]

MKS1 Gene-Disease associations (from GenCC):

• Bardet-Biedl syndrome 13

  Inheritance: AR, Unknown Classification: DEFINITIVE, STRONG, LIMITED Submitted by: G2P, Genomics England PanelApp, Labcorp Genetics (formerly Invitae)
• ciliopathy

  Inheritance: AR Classification: DEFINITIVE Submitted by: ClinGen
• Meckel syndrome, type 1

  Inheritance: AR Classification: DEFINITIVE, STRONG Submitted by: Labcorp Genetics (formerly Invitae), Myriad Women’s Health
• Joubert syndrome 28

  Inheritance: AR Classification: STRONG Submitted by: Labcorp Genetics (formerly Invitae)
• Bardet-Biedl syndrome

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet
• Joubert syndrome

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet
• Joubert syndrome with ocular defect

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet
• Meckel syndrome

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Likely_pathogenic. The variant received 8 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PM5: Other missense variant is known to change same aminoacid residue: Variant chr17-58210980-C-T is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 56627.
• PP3: Splicing predictors support a deleterious effect. Scorers claiming Pathogenic: dbscSNV1_ADA, dbscSNV1_RF, max_spliceai. No scorers claiming Uncertain. No scorers claiming Benign.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_017777.4. 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
	MKS1	NM_017777.4	MANE Select	c.958G>C	p.Val320Leu	missense splice_region	Exon 10 of 18	NP_060247.2	Q9NXB0-1
	MKS1	NM_001321269.2		c.958G>C	p.Val320Leu	missense splice_region	Exon 10 of 17	NP_001308198.1	A0A7I2V2M0
	MKS1	NM_001330397.2		c.958G>C	p.Val320Leu	missense splice_region	Exon 10 of 16	NP_001317326.1	H0Y2S2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	MKS1	ENST00000393119.7	TSL:1 MANE Select	c.958G>C	p.Val320Leu	missense splice_region	Exon 10 of 18	ENSP00000376827.2	Q9NXB0-1
	MKS1	ENST00000537529.7	TSL:1	c.529G>C	p.Val177Leu	missense splice_region	Exon 10 of 18	ENSP00000442096.3	A0A0S2Z5Z2
	MKS1	ENST00000966002.1		c.958G>C	p.Val320Leu	missense splice_region	Exon 10 of 18	ENSP00000636061.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.31
BayesDel_addAF	Pathogenic	0.22	D
BayesDel_noAF	Uncertain	0.070
CADD	Pathogenic	33
DANN	Uncertain	1.0
DEOGEN2	Benign	0.24	T
Eigen	Uncertain	0.57
Eigen_PC	Uncertain	0.60
FATHMM_MKL	Uncertain	0.97	D
LIST_S2	Uncertain	0.93	D
M_CAP	Uncertain	0.11	D
MetaRNN	Benign	0.39	T
MetaSVM	Uncertain	-0.17	T
MutationAssessor	Benign	2.0	M
PhyloP100		4.7
PrimateAI	Uncertain	0.73	T
PROVEAN	Benign	-1.3	N
REVEL	Uncertain	0.36
Sift	Uncertain	0.015	D
Sift4G	Pathogenic	0.0	D
Polyphen		0.66	P
Vest4		0.69
MutPred		0.54		Loss of sheet (P = 0.1501)
MVP		0.88
MPC		0.45
ClinPred		0.89	D
GERP RS		5.5
Varity_R		0.67
gMVP		0.41
Mutation Taster		=26/74	disease causing

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Pathogenic	1.0
dbscSNV1_RF	Pathogenic	0.98
SpliceAI score (max)		0.81		Details are displayed if max score is > 0.2
DS_DL_spliceai		0.81		Position offset: 0

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs386834053; hg19: chr17-56288341;