rs864309696

Variant names:

• chr12-56453080-T-TAGTGGAATGTTCCC
• rs864309696
• NM_012064.4:c.597_598insGGGAACATTCCACT

Variant summary

Our verdict is Uncertain significance. The variant received 5 ACMG points: 5P and 0B. PVS1_Strong PP5

The NM_012064.4(MIP):​c.597_598insGGGAACATTCCACT​(p.Asn200GlyfsTer12) variant causes a frameshift change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. It is difficult to determine the true allele frequency of this variant because it is of type INS_BIG, and the frequency of such variant types in population databases may be underestimated and unreliable. Variant has been reported in ClinVar as Pathogenic (no stars).

• Frequency: Genomes: not found (cov: 32)
• Consequence: MIP NM_012064.4 frameshift
• Clinical Significance: Pathogenic no assertion criteria provided P:1
• Conservation: PhyloP100: 2.18
• Publications: 0 publications found

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 Gene-Disease associations (from GenCC):

• cataract 15 multiple types

  Inheritance: AD Classification: DEFINITIVE, STRONG Submitted by: G2P, Labcorp Genetics (formerly Invitae), Ambry Genetics
• cerulean cataract

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• early-onset lamellar cataract

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• early-onset nuclear cataract

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• early-onset posterior polar cataract

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• early-onset sutural cataract

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• total early-onset cataract

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet

ENSG00000285528 (HGNC:):

ACMG classification

Our verdict: Uncertain_significance. The variant received 5 ACMG points.

• PVS1: Loss of function variant, product does not undergo nonsense mediated mRNA decay. Variant is located in the 3'-most 50 bp of the penultimate exon, not predicted to undergo nonsense mediated mRNA decay. There are 9 pathogenic variants in the truncated region.
• PP5: Variant 12-56453080-T-TAGTGGAATGTTCCC is Pathogenic according to our data. Variant chr12-56453080-T-TAGTGGAATGTTCCC is described in ClinVar as Pathogenic. ClinVar VariationId is 217345.Status of the report is no_assertion_criteria_provided, 0 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
MIP	NM_012064.4	c.597_598insGGGAACATTCCACT	p.Asn200GlyfsTer12	frameshift_variant	Exon 3 of 4	ENST00000652304.1	NP_036196.1
MIP	XM_011538354.2	c.312_313insGGGAACATTCCACT	p.Asn105GlyfsTer12	frameshift_variant	Exon 5 of 6		XP_011536656.1
MIP	XM_017019306.2	c.240_241insGGGAACATTCCACT	p.Asn81GlyfsTer12	frameshift_variant	Exon 3 of 4		XP_016874795.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
MIP	ENST00000652304.1	c.597_598insGGGAACATTCCACT	p.Asn200GlyfsTer12	frameshift_variant	Exon 3 of 4		NM_012064.4	ENSP00000498622.1
ENSG00000285528	ENST00000648304.1	n.*221_*222insGGGAACATTCCACT		non_coding_transcript_exon_variant	Exon 3 of 4			ENSP00000497190.1
ENSG00000285528	ENST00000648304.1	n.*221_*222insGGGAACATTCCACT		3_prime_UTR_variant	Exon 3 of 4			ENSP00000497190.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 29

GnomAD4 genome Cov.: 32

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:1

Revision: no assertion criteria provided

Submissions by phenotype

Developmental cataract Pathogenic:1

Jan 09, 2015

Eye Genetics Research Group, Children's Medical Research Institute

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: research

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
PhyloP100		2.2
Mutation Taster		=3/197	disease causing (ClinVar)

Splicing

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

Other links and lift over

dbSNP: rs864309696; hg19: chr12-56846864;