chr12-56450775-A-G

Variant names:

• chr12-56450775-A-G
• rs774053
• ENST00000648304.1:n.*921T>C

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BA1

The ENST00000648304.1(ENSG00000285528):​n.*921T>C variant causes a non coding transcript exon change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.85 in 163,274 control chromosomes in the GnomAD database, including 60,703 homozygotes. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: 𝑓 0.84 (55678 hom., cov: 30)
  • Exomes 𝑓: 0.94 (5025 hom.)
• Consequence: ENSG00000285528 ENST00000648304.1 non_coding_transcript_exon
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 0.466
• Publications: 6 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: Benign. The variant received -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.77).
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.972 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
MIP	NM_012064.4	c.*505T>C		3_prime_UTR_variant	Exon 4 of 4	ENST00000652304.1	NP_036196.1
MIP	XM_011538354.2	c.*505T>C		3_prime_UTR_variant	Exon 6 of 6		XP_011536656.1
MIP	XM_017019306.2	c.*505T>C		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.*921T>C		non_coding_transcript_exon_variant	Exon 4 of 4			ENSP00000497190.1
MIP	ENST00000652304.1	c.*505T>C		3_prime_UTR_variant	Exon 4 of 4		NM_012064.4	ENSP00000498622.1
ENSG00000285528	ENST00000648304.1	n.*921T>C		3_prime_UTR_variant	Exon 4 of 4			ENSP00000497190.1

Frequencies

GnomAD3 genomes AF: 0.844 AC: 128104 AN: 151834 Hom.: 55666 Cov.: 30

Gnomad AFR AF: 0.608

Gnomad AMI AF: 0.934

Gnomad AMR AF: 0.913

Gnomad ASJ AF: 0.889

Gnomad EAS AF: 0.995

Gnomad SAS AF: 0.954

Gnomad FIN AF: 0.934

Gnomad MID AF: 0.832

Gnomad NFE AF: 0.933

Gnomad OTH AF: 0.868

GnomAD4 exome AF: 0.941 AC: 10653 AN: 11322 Hom.: 5025 Cov.: 0 AF XY: 0.943 AC XY: 5822 AN XY: 6172

African (AFR) AF: 0.482 AC: 27 AN: 56

American (AMR) AF: 0.933 AC: 1840 AN: 1972

Ashkenazi Jewish (ASJ) AF: 0.823 AC: 79 AN: 96

East Asian (EAS) AF: 1.00 AC: 362 AN: 362

South Asian (SAS) AF: 0.961 AC: 1540 AN: 1602

European-Finnish (FIN) AF: 0.932 AC: 505 AN: 542

Middle Eastern (MID) AF: 0.833 AC: 10 AN: 12

European-Non Finnish (NFE) AF: 0.944 AC: 5880 AN: 6232

Other (OTH) AF: 0.915 AC: 410 AN: 448

GnomAD4 genome AF: 0.843 AC: 128156 AN: 151952 Hom.: 55678 Cov.: 30 AF XY: 0.850 AC XY: 63113 AN XY: 74288

African (AFR) AF: 0.608 AC: 25125 AN: 41330

American (AMR) AF: 0.913 AC: 13937 AN: 15266

Ashkenazi Jewish (ASJ) AF: 0.889 AC: 3085 AN: 3470

East Asian (EAS) AF: 0.995 AC: 5147 AN: 5174

South Asian (SAS) AF: 0.955 AC: 4597 AN: 4816

European-Finnish (FIN) AF: 0.934 AC: 9880 AN: 10578

Middle Eastern (MID) AF: 0.837 AC: 246 AN: 294

European-Non Finnish (NFE) AF: 0.933 AC: 63460 AN: 68004

Other (OTH) AF: 0.867 AC: 1829 AN: 2110

Alfa AF: 0.874 Hom.: 23876

Bravo AF: 0.832

Asia WGS AF: 0.944 AC: 3282 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:1

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Cataract 15 multiple types Benign:1

Apr 27, 2017

Illumina Laboratory Services, Illumina

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). No publications were found based on this search. Allele frequency data from public databases was too high to be consistent with this variant causing disease. Therefore, this variant is classified as benign. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.77
CADD	Benign	6.9
DANN	Benign	0.76
PhyloP100		0.47
Mutation Taster		=100/0	polymorphism (auto)

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

Other links and lift over

dbSNP: rs774053; hg19: chr12-56844559;