12-56453715-T-G

Position:

• chr12-56453715-T-G

Variant summary

Our verdict is Pathogenic. Variant got 10 ACMG points: 10P and 0B. PM1 PM2 PP3_Strong PP5_Moderate

The NM_012064.4(MIP):​c.401A>C​(p.Glu134Ala) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: MIP NM_012064.4 missense
• Clinical Significance: Likely pathogenic criteria provided, single submitter P:1
• Conservation: PhyloP100: 7.67

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]

ACMG classification

Verdict is Pathogenic. Variant got 10 ACMG points.

• PM1: In a chain Lens fiber major intrinsic protein (size 262) in uniprot entity MIP_HUMAN there are 9 pathogenic changes around while only 0 benign (100%) in NM_012064.4
• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.994
• PP5: Variant 12-56453715-T-G is Pathogenic according to our data. Variant chr12-56453715-T-G is described in ClinVar as [Likely_pathogenic]. Clinvar id is 391974.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
MIP	NM_012064.4	c.401A>C	p.Glu134Ala	missense_variant	2/4	ENST00000652304.1	NP_036196.1
MIP	XM_011538354.2	c.116A>C	p.Glu39Ala	missense_variant	4/6		XP_011536656.1
MIP	XM_017019306.2	c.44A>C	p.Glu15Ala	missense_variant	2/4		XP_016874795.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
MIP	ENST00000652304.1	c.401A>C	p.Glu134Ala	missense_variant	2/4		NM_012064.4	ENSP00000498622	P1
MIP	ENST00000555551.1	n.357A>C		non_coding_transcript_exon_variant	2/3	1
MIP	ENST00000648442.1	n.534A>C		non_coding_transcript_exon_variant	4/6
MIP	ENST00000650166.1	n.290A>C		non_coding_transcript_exon_variant	3/5

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 32

ClinVar

Significance: Likely pathogenic

Submissions summary: Pathogenic:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

GeneDx

Jan 09, 2017

The E134A variant in the MIP gene has not been reported previously as a pathogenic variant, nor as abenign variant, to our knowledge. However, a missense variant at this same codon (E134G) has beenreported in a large family with autosomal dominant congenital cataracts (Berry et al., 2000). TheE134A variant was not observed in approximately 6500 individuals of European and AfricanAmerican ancestry in the NHLBI Exome Sequencing Project, indicating it is not a common benignvariant in these populations. The E134A variant is a non-conservative amino acid substitution, whichis likely to impact secondary protein structure as these residues differ in polarity, charge, size and/orother properties. In addition, this substitution occurs at a position that is conserved across species, andin silico analysis predicts this variant is probably damaging to the protein structure/function. TheE134A variant is a strong candidate for a pathogenic variant, however the possibility it may be a rarebenign variant cannot be excluded. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.98
BayesDel_addAF	Pathogenic	0.57	D
BayesDel_noAF	Pathogenic	0.58
CADD	Pathogenic	26
DANN	Uncertain	0.99
DEOGEN2	Pathogenic	0.95	D
Eigen	Pathogenic	0.98
Eigen_PC	Pathogenic	0.85
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.96	D
M_CAP	Pathogenic	0.76	D
MetaRNN	Pathogenic	0.99	D
MetaSVM	Pathogenic	1.1	D
MutationAssessor	Pathogenic	4.4	H
MutationTaster	Benign	1.0	D
PrimateAI	Uncertain	0.69	T
PROVEAN	Pathogenic	-5.7	D
REVEL	Pathogenic	0.99
Sift	Pathogenic	0.0	D
Sift4G	Pathogenic	0.0	D
Polyphen		1.0	D
Vest4		0.97
MutPred		0.91		Gain of glycosylation at T131 (P = 0.1702);
MVP		0.98
MPC		1.3
ClinPred		1.0	D
GERP RS		4.8
Varity_R		0.95

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: rs121917869; hg19: chr12-56847499;