rs398122378

Variant summary

Our verdict is Pathogenic. Variant got 14 ACMG points: 14P and 0B. PVS1_StrongPM2PP5_Very_Strong

The NM_012064.4(MIP):c.638del(p.Gly213ValfsTer46) variant causes a frameshift change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000684 in 1,461,840 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Likely pathogenic (★★).

Frequency

Genomes: not found (cov: 32)

Exomes 𝑓: 6.8e-7 ( 0 hom. )

Consequence

MIP
NM_012064.4 frameshift

Scores

Not classified

Clinical Significance

Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:6

Conservation

PhyloP100: 2.75

Variant links:

Genes affected

MIP (HGNC:7103): (major intrinsic protein of lens fiber) Major intrinsic protein is a member of the water-transporting aquaporins as well as the original member of the MIP family of channel proteins. The function of the fiber cell membrane protein encoded by this gene is undetermined, yet this protein is speculated to play a role in intracellular communication. The MIP protein is expressed in the ocular lens and is required for correct lens function. This gene has been mapped among aquaporins AQP2, AQP5, and AQP6, in a potential gene cluster at 12q13. [provided by RefSeq, Jul 2008]

MIP links:

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ACMG classification

Classification made for transcript

Verdict is Pathogenic. Variant got 14 ACMG points.

PVS1

Loss of function variant, product does not undergo nonsense mediated mRNA decay. Variant is located in the 3'-most exon, not predicted to undergo nonsense mediated mRNA decay. Fraction of 0.194 CDS is truncated, and there are 2 pathogenic variants in the truncated region.

PM2

Very rare variant in population databases, with high coverage;

PP5

Variant 12-56451433-AC-A is Pathogenic according to our data. Variant chr12-56451433-AC-A is described in ClinVar as [Likely_pathogenic]. Clinvar id is 50960.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE
MIP	NM_012064.4 linkuse as main transcript	c.638del	p.Gly213ValfsTer46	frameshift_variant	4/4	ENST00000652304.1
MIP	XM_011538354.2 linkuse as main transcript	c.353del	p.Gly118ValfsTer46	frameshift_variant	6/6
MIP	XM_017019306.2 linkuse as main transcript	c.281del	p.Gly94ValfsTer46	frameshift_variant	4/4

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Appris
MIP	ENST00000652304.1 linkuse as main transcript	c.638del	p.Gly213ValfsTer46	frameshift_variant	4/4	NM_012064.4	P1
MIP	ENST00000648442.1 linkuse as main transcript	n.771del		non_coding_transcript_exon_variant	6/6
MIP	ENST00000650166.1 linkuse as main transcript	n.527del		non_coding_transcript_exon_variant	5/5

Frequencies

GnomAD3 genomes

Cov.:

GnomAD3 exomes

AF:

0.00000401

AC:

AN:

249660

Hom.:

AF XY:

0.00

AC XY:

AN XY:

135100

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

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:

0.00000893

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

6.84e-7

AC:

AN:

1461840

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

727204

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.00

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:

8.99e-7

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

Cov.:

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:6

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Cataract 15 multiple types

Pathogenic:3

Pathogenic, criteria provided, single submitter	clinical testing	Greenwood Genetic Center Diagnostic Laboratories, Greenwood Genetic Center	Aug 23, 2021	PVS1, PS3, PM2 -
Pathogenic, no assertion criteria provided	literature only	OMIM	Apr 01, 2006	- -
Pathogenic, criteria provided, single submitter	clinical testing	Invitae	Nov 13, 2023	This sequence change creates a premature translational stop signal (p.Gly213Valfs*46) in the MIP gene. While this is not anticipated to result in nonsense mediated decay, it is expected to disrupt the last 51 amino acid(s) of the MIP protein. This variant is present in population databases (rs398122378, gnomAD 0.0009%). This premature translational stop signal has been observed in individuals with congenital cataracts (PMID: 16564824; Invitae). It has also been observed to segregate with disease in related individuals. This variant is also known as Nt 3223del G. ClinVar contains an entry for this variant (Variation ID: 50960). Algorithms developed to predict the effect of variants on protein structure and function are not available or were not evaluated for this variant. Experimental studies have shown that this premature translational stop signal affects MIP function (PMID: 18501347). For these reasons, this variant has been classified as Pathogenic. -

Inborn genetic diseases

Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

Ambry Genetics

Oct 13, 2023

The c.638delG (p.G213Vfs*46) alteration, located in exon 4 (coding exon 4) of the MIP gene, consists of a deletion of one nucleotide at position 638, causing a translational frameshift with a predicted alternate stop codon after 46 amino acids. This alteration is expected to result in premature protein truncation or nonsense-mediated mRNA decay. However, loss of function of MIP has not been established as a mechanism of disease. Based on data from gnomAD, this allele has an overall frequency of <0.001% (1/249660) total alleles studied. The highest observed frequency was 0.001% (1/111956) of European (non-Finnish) alleles. This variant has been found to segregate with disease in multiple family members affected with congenital cataracts (Geyer, 2006). Functional studies demonstrated that this variant is non-functional due to its failure to properly traffic to the plasma membrane and induce cell death by necrosis through the loss of cell membrane integrity (Varadaraj, 2008). In another study, this variant did not significantly alter the localization and reduce cell proliferation compared to the wildtype MIP protein (Xiu, 2019). Based on the available evidence, this alteration is classified as likely pathogenic. -

not provided

Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

GeneDx

Mar 01, 2022

Frameshift variant predicted to result in protein truncation, as the last 51 amino acids are replaced with 45 different amino acids, and other loss-of-function variants have been reported downstream in HGMD; Not observed at significant frequency in large population cohorts (gnomAD); Published functional studies are discrepant regarding the effect of the variant on protein localization and function (Varadaraj et al., 2008; Xiu et al., 2019); This variant is associated with the following publications: (PMID: 16564824, 18501347, 30585525, 10937580) -

MIP-related disorder

Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Dec 20, 2023

The MIP c.638delG variant is predicted to result in a frameshift and premature protein termination (p.Gly213Valfs*46). This variant has been reported as segregating with disease in a large kindred with autosomal dominant cataracts (referred to as nt 3223 in Geyer et al. 2006. PubMed ID: 16564824). Functional studies using protein expression in xenopus oocytes showed that this variant leads to protein retention in the endoplasmic reticulum (ER), preventing trafficking to the plasma membrane and decreasing cell membrane water permeability (Varadaraj et al. 2008. PubMed ID: 18501347). This variant is reported in 0.00089% of alleles in individuals of European (Non-Finnish) descent in gnomAD. Frameshift variants in MIP are expected to be pathogenic, and this variant has been classified as pathogenic by multiple independent submitters to the ClinVar database (https://www.ncbi.nlm.nih.gov/clinvar/variation/50960). Given the evidence, we interpret c.638del (p.Gly213Valfs*46) as pathogenic. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over