rs1057519616

Positions:

• chr12-56453607-A-AG

Variant summary

Our verdict is Pathogenic. Variant got 11 ACMG points: 11P and 0B. PVS1 PM2 PP5

The NM_012064.4(MIP):​c.508_509insC​(p.Leu170ProfsTer31) variant causes a frameshift change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Pathogenic (no stars). Variant results in nonsense mediated mRNA decay.

• Frequency: Genomes: not found (cov: 32)
• Consequence: MIP NM_012064.4 frameshift
• Clinical Significance: Pathogenic no assertion criteria provided P:1
• Conservation: PhyloP100: 0.677

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 11 ACMG points.

• PVS1: Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 12-56453607-A-AG is Pathogenic according to our data. Variant chr12-56453607-A-AG is described in ClinVar as [Pathogenic]. Clinvar id is 377392.Status of the report is no_assertion_criteria_provided, 0 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
MIP	NM_012064.4	c.508_509insC	p.Leu170ProfsTer31	frameshift_variant	2/4	ENST00000652304.1	NP_036196.1
MIP	XM_011538354.2	c.223_224insC	p.Leu75ProfsTer31	frameshift_variant	4/6		XP_011536656.1
MIP	XM_017019306.2	c.151_152insC	p.Leu51ProfsTer31	frameshift_variant	2/4		XP_016874795.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
MIP	ENST00000652304.1	c.508_509insC	p.Leu170ProfsTer31	frameshift_variant	2/4		NM_012064.4	ENSP00000498622	P1
MIP	ENST00000555551.1	n.464_465insC		non_coding_transcript_exon_variant	2/3	1
MIP	ENST00000648442.1	n.641_642insC		non_coding_transcript_exon_variant	4/6
MIP	ENST00000650166.1	n.397_398insC		non_coding_transcript_exon_variant	3/5

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 32

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:1

Revision: no assertion criteria provided

Submissions by phenotype

Cataract 15 multiple types Pathogenic:1

Pathogenic, no assertion criteria provided

clinical testing

Medical Genetic Institute of Henan Province, Henan Provincial People’s Hospital

Dec 16, 2015

- -

Computational scores

Source: dbNSFP v4.3

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: rs1057519616; hg19: chr12-56847391;