12-56450041-C-CAA

Variant names:

• chr12-56450041-C-CAA
• rs111463603
• ENST00000648304.1:n.*1653_*1654dupTT

Variant summary

Our verdict is Likely benign. The variant received -5 ACMG points: 0P and 5B. BS1_Supporting BS2

The ENST00000648304.1(ENSG00000285528):​n.*1653_*1654dupTT variant causes a non coding transcript exon change involving the alteration of a non-conserved nucleotide. Variant has been reported in ClinVar as Uncertain significance (★★).

• Frequency:
  • Genomes: 𝑓 0.019 (29 hom., cov: 0)
  • Failed GnomAD Quality Control
• Consequence: ENSG00000285528 ENST00000648304.1 non_coding_transcript_exon
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:2
• Conservation: PhyloP100: 0.669
• Publications: 1 publications found

Genes affected

ENSG00000285528 (HGNC:):

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

ACMG classification

Our verdict: Likely_benign. The variant received -5 ACMG points.

• BS1: Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.0189 (2764/146482) while in subpopulation NFE AF = 0.0264 (1754/66556). AF 95% confidence interval is 0.0253. There are 29 homozygotes in GnomAd4. There are 1364 alleles in the male GnomAd4 subpopulation. Median coverage is 0. This position passed quality control check. Existence of Clinvar submissions makes me limit the strength of this signal to Supporting
• BS2: High Homozygotes in GnomAd4 at 29 gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
MIP	NM_012064.4	c.*1237_*1238dupTT		3_prime_UTR_variant	Exon 4 of 4	ENST00000652304.1	NP_036196.1
MIP	XM_011538354.2	c.*1237_*1238dupTT		3_prime_UTR_variant	Exon 6 of 6		XP_011536656.1
MIP	XM_017019306.2	c.*1237_*1238dupTT		3_prime_UTR_variant	Exon 4 of 4		XP_016874795.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ENSG00000285528	ENST00000648304.1	n.*1653_*1654dupTT		non_coding_transcript_exon_variant	Exon 4 of 4			ENSP00000497190.1
MIP	ENST00000652304.1	c.*1237_*1238dupTT		3_prime_UTR_variant	Exon 4 of 4		NM_012064.4	ENSP00000498622.1
ENSG00000285528	ENST00000648304.1	n.*1653_*1654dupTT		3_prime_UTR_variant	Exon 4 of 4			ENSP00000497190.1

Frequencies

GnomAD3 genomes AF: 0.0188 AC: 2759 AN: 146408 Hom.: 29 Cov.: 0

Gnomad AFR AF: 0.00754

Gnomad AMI AF: 0.00551

Gnomad AMR AF: 0.0186

Gnomad ASJ AF: 0.0305

Gnomad EAS AF: 0.00354

Gnomad SAS AF: 0.00816

Gnomad FIN AF: 0.0240

Gnomad MID AF: 0.0130

Gnomad NFE AF: 0.0263

Gnomad OTH AF: 0.0244

GnomAD4 exome Data not reliable, filtered out with message: AC0 AC: 0 AN: 0 Hom.: 0 Cov.: 0 AC XY: 0 AN XY: 0

African (AFR) AC: 0 AN: 0

American (AMR) AC: 0 AN: 0

Ashkenazi Jewish (ASJ) AC: 0 AN: 0

East Asian (EAS) AC: 0 AN: 0

South Asian (SAS) AC: 0 AN: 0

European-Finnish (FIN) AC: 0 AN: 0

Middle Eastern (MID) AC: 0 AN: 0

European-Non Finnish (NFE) AC: 0 AN: 0

Other (OTH) AC: 0 AN: 0

GnomAD4 genome AF: 0.0189 AC: 2764 AN: 146482 Hom.: 29 Cov.: 0 AF XY: 0.0192 AC XY: 1364 AN XY: 71062

African (AFR) AF: 0.00758 AC: 303 AN: 39994

American (AMR) AF: 0.0186 AC: 273 AN: 14708

Ashkenazi Jewish (ASJ) AF: 0.0305 AC: 105 AN: 3442

East Asian (EAS) AF: 0.00355 AC: 18 AN: 5074

South Asian (SAS) AF: 0.00862 AC: 40 AN: 4642

European-Finnish (FIN) AF: 0.0240 AC: 212 AN: 8844

Middle Eastern (MID) AF: 0.0141 AC: 4 AN: 284

European-Non Finnish (NFE) AF: 0.0264 AC: 1754 AN: 66556

Other (OTH) AF: 0.0246 AC: 50 AN: 2030

Alfa AF: 0.0195 Hom.: 2029

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Cataract Uncertain:1

Jun 14, 2016

Illumina Laboratory Services, Illumina

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

not provided Uncertain:1

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
PhyloP100		0.67
Mutation Taster		=100/0	polymorphism

Splicing

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

Other links and lift over

dbSNP: rs111463603; hg19: chr12-56843825;