17-58216714-G-C

Variant names:

• chr17-58216714-G-C
• rs142813109
• NM_017777.4:c.213C>G

Variant summary

Our verdict is Benign. The variant received -9 ACMG points: 0P and 9B. BP4_Strong BP6 BS2

The NM_017777.4(MKS1):​c.213C>G​(p.Asp71Glu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00515 in 1,614,110 control chromosomes in the GnomAD database, including 28 homozygotes. In-silico tool predicts a benign outcome for this variant. 17/22 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. D71D) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.0032 (0 hom., cov: 32)
  • Exomes 𝑓: 0.0054 (28 hom.)
• Consequence: MKS1 NM_017777.4 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:2 B:13
• Conservation: PhyloP100: -0.690
• Publications: 9 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):

• 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
• Bardet-Biedl syndrome 13

  Inheritance: Unknown, AR Classification: DEFINITIVE, STRONG, LIMITED Submitted by: Labcorp Genetics (formerly Invitae), Genomics England PanelApp, G2P
• 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: Benign. The variant received -9 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0042831004).
• BP6: Variant 17-58216714-G-C is Benign according to our data. Variant chr17-58216714-G-C is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 196477.
• BS2: High Homozygotes in GnomAdExome4 at 28 AR,Unknown gene

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.213C>G	p.Asp71Glu	missense	Exon 3 of 18	NP_060247.2	Q9NXB0-1
	MKS1	NM_001321269.2		c.213C>G	p.Asp71Glu	missense	Exon 3 of 17	NP_001308198.1	A0A7I2V2M0
	MKS1	NM_001330397.2		c.213C>G	p.Asp71Glu	missense	Exon 3 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.213C>G	p.Asp71Glu	missense	Exon 3 of 18	ENSP00000376827.2	Q9NXB0-1
	MKS1	ENST00000537529.7	TSL:1	c.-217C>G		5_prime_UTR	Exon 3 of 18	ENSP00000442096.3	A0A0S2Z5Z2
	MKS1	ENST00000966002.1		c.213C>G	p.Asp71Glu	missense	Exon 3 of 18	ENSP00000636061.1

Frequencies

GnomAD3 genomes AF: 0.00320 AC: 487 AN: 152174 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.00140

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00164

Gnomad ASJ AF: 0.000576

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000207

Gnomad FIN AF: 0.00132

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00563

Gnomad OTH AF: 0.00191

GnomAD2 exomes AF: 0.00315 AC: 785 AN: 249528 AF XY: 0.00314

Gnomad AFR exome AF: 0.00142

Gnomad AMR exome AF: 0.00246

Gnomad ASJ exome AF: 0.000496

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00209

Gnomad NFE exome AF: 0.00520

Gnomad OTH exome AF: 0.00495

GnomAD4 exome AF: 0.00535 AC: 7823 AN: 1461818 Hom.: 28 Cov.: 32 AF XY: 0.00517 AC XY: 3757 AN XY: 727220

African (AFR) AF: 0.00108 AC: 36 AN: 33480

American (AMR) AF: 0.00226 AC: 101 AN: 44720

Ashkenazi Jewish (ASJ) AF: 0.000536 AC: 14 AN: 26136

East Asian (EAS) AF: 0.0000252 AC: 1 AN: 39700

South Asian (SAS) AF: 0.000533 AC: 46 AN: 86248

European-Finnish (FIN) AF: 0.00227 AC: 121 AN: 53418

Middle Eastern (MID) AF: 0.000347 AC: 2 AN: 5768

European-Non Finnish (NFE) AF: 0.00651 AC: 7235 AN: 1111954

Other (OTH) AF: 0.00442 AC: 267 AN: 60394

GnomAD4 genome AF: 0.00318 AC: 485 AN: 152292 Hom.: 0 Cov.: 32 AF XY: 0.00309 AC XY: 230 AN XY: 74468

African (AFR) AF: 0.00140 AC: 58 AN: 41570

American (AMR) AF: 0.00157 AC: 24 AN: 15296

Ashkenazi Jewish (ASJ) AF: 0.000576 AC: 2 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5186

South Asian (SAS) AF: 0.000207 AC: 1 AN: 4822

European-Finnish (FIN) AF: 0.00132 AC: 14 AN: 10612

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

European-Non Finnish (NFE) AF: 0.00562 AC: 382 AN: 68014

Other (OTH) AF: 0.00189 AC: 4 AN: 2116

Alfa AF: 0.00473 Hom.: 0

Bravo AF: 0.00348

TwinsUK AF: 0.00809 AC: 30

ALSPAC AF: 0.00727 AC: 28

ESP6500AA AF: 0.00202 AC: 8

ESP6500EA AF: 0.00578 AC: 48

ExAC AF: 0.00330 AC: 399

EpiCase AF: 0.00518

EpiControl AF: 0.00480

ClinVar

ClinVar submissions

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
-	-	6	not provided (6)
-	-	3	not specified (3)
-	1	1	Bardet-Biedl syndrome 13 (2)
-	1	1	Meckel syndrome, type 1 (2)
-	-	1	Meckel-Gruber syndrome;C5979921:Joubert syndrome (1)
-	-	1	MKS1-related disorder (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.075
BayesDel_addAF	Benign	-0.55	T
BayesDel_noAF	Benign	-0.55
CADD	Benign	7.6
DANN	Benign	0.97
DEOGEN2	Benign	0.14	T
Eigen	Benign	-0.75
Eigen_PC	Benign	-0.73
FATHMM_MKL	Benign	0.17	N
LIST_S2	Benign	0.69	T
M_CAP	Benign	0.012	T
MetaRNN	Benign	0.0043	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	-0.17	N
PhyloP100		-0.69
PrimateAI	Benign	0.32	T
PROVEAN	Benign	-0.11	N
REVEL	Benign	0.065
Sift	Benign	0.92	T
Sift4G	Benign	1.0	T
Polyphen		0.0	B
Vest4		0.22
MutPred		0.21		Gain of helix (P = 0.0325)
MVP		0.72
MPC		0.23
ClinPred		0.0085	T
GERP RS		-3.3
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		2.8
Varity_R		0.022
gMVP		0.13
Mutation Taster		=99/1	polymorphism

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: rs142813109; hg19: chr17-56294075; COSMIC: COSV58306622; COSMIC: COSV58306622;