12-56450775-A-G

Position:

• chr12-56450775-A-G

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_012064.4(MIP):​c.*505T>C variant causes a 3 prime UTR 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. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.84 (55678 hom., cov: 30)
  • Exomes 𝑓: 0.94 (5025 hom.)
• Consequence: MIP NM_012064.4 3_prime_UTR
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 0.466

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 Benign. Variant got -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.77).
• BP6: Variant 12-56450775-A-G is Benign according to our data. Variant chr12-56450775-A-G is described in ClinVar as [Benign]. Clinvar id is 309875.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• 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/exons	MANE	UniProt
MIP	NM_012064.4	c.*505T>C		3_prime_UTR_variant	4/4	ENST00000652304.1
MIP	XM_011538354.2	c.*505T>C		3_prime_UTR_variant	6/6
MIP	XM_017019306.2	c.*505T>C		3_prime_UTR_variant	4/4

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
MIP	ENST00000652304.1	c.*505T>C		3_prime_UTR_variant	4/4		NM_012064.4	P1

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

Gnomad4 AFR exome AF: 0.482

Gnomad4 AMR exome AF: 0.933

Gnomad4 ASJ exome AF: 0.823

Gnomad4 EAS exome AF: 1.00

Gnomad4 SAS exome AF: 0.961

Gnomad4 FIN exome AF: 0.932

Gnomad4 NFE exome AF: 0.944

Gnomad4 OTH exome AF: 0.915

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

Gnomad4 AFR AF: 0.608

Gnomad4 AMR AF: 0.913

Gnomad4 ASJ AF: 0.889

Gnomad4 EAS AF: 0.995

Gnomad4 SAS AF: 0.955

Gnomad4 FIN AF: 0.934

Gnomad4 NFE AF: 0.933

Gnomad4 OTH AF: 0.867

Alfa AF: 0.867 Hom.: 13638

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

Cataract 15 multiple types Benign:1

Benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Apr 27, 2017

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. -

not provided Benign:1

Benign, criteria provided, single submitter

not provided

Breakthrough Genomics, Breakthrough Genomics

-

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.77
CADD	Benign	6.9
DANN	Benign	0.76

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: rs774053; hg19: chr12-56844559;