12-56450789-T-G

Variant names:

• chr12-56450789-T-G
• rs137926387
• ENST00000648304.1:n.*907A>C

Variant summary

Our verdict is Likely benign. The variant received -6 ACMG points: 0P and 6B. BP4_Strong BP6_Moderate

The ENST00000648304.1(ENSG00000285528):​n.*907A>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 0.00222 in 167,844 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

• Frequency:
  • Genomes: 𝑓 0.0022 (1 hom., cov: 30)
  • Exomes 𝑓: 0.0023 (0 hom.)
• Consequence: ENSG00000285528 ENST00000648304.1 non_coding_transcript_exon
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: -0.153
• Publications: 0 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 -6 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.74).
• BP6: Variant 12-56450789-T-G is Benign according to our data. Variant chr12-56450789-T-G is described in ClinVar as [Benign]. Clinvar id is 309876.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
MIP	NM_012064.4	c.*491A>C		3_prime_UTR_variant	Exon 4 of 4	ENST00000652304.1	NP_036196.1
MIP	XM_011538354.2	c.*491A>C		3_prime_UTR_variant	Exon 6 of 6		XP_011536656.1
MIP	XM_017019306.2	c.*491A>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.*907A>C		non_coding_transcript_exon_variant	Exon 4 of 4			ENSP00000497190.1
MIP	ENST00000652304.1	c.*491A>C		3_prime_UTR_variant	Exon 4 of 4		NM_012064.4	ENSP00000498622.1
ENSG00000285528	ENST00000648304.1	n.*907A>C		3_prime_UTR_variant	Exon 4 of 4			ENSP00000497190.1

Frequencies

GnomAD3 genomes AF: 0.00221 AC: 336 AN: 152124 Hom.: 1 Cov.: 30

Gnomad AFR AF: 0.000773

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00426

Gnomad ASJ AF: 0.00202

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000414

Gnomad FIN AF: 0.00104

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00312

Gnomad OTH AF: 0.00334

GnomAD4 exome AF: 0.00231 AC: 36 AN: 15602 Hom.: 0 Cov.: 0 AF XY: 0.00177 AC XY: 15 AN XY: 8474

African (AFR) AF: 0.00 AC: 0 AN: 108

American (AMR) AF: 0.00419 AC: 10 AN: 2384

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 158

East Asian (EAS) AF: 0.00 AC: 0 AN: 586

South Asian (SAS) AF: 0.000434 AC: 1 AN: 2306

European-Finnish (FIN) AF: 0.00551 AC: 4 AN: 726

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 28

European-Non Finnish (NFE) AF: 0.00243 AC: 21 AN: 8658

Other (OTH) AF: 0.00 AC: 0 AN: 648

GnomAD4 genome AF: 0.00221 AC: 336 AN: 152242 Hom.: 1 Cov.: 30 AF XY: 0.00214 AC XY: 159 AN XY: 74436

African (AFR) AF: 0.000771 AC: 32 AN: 41524

American (AMR) AF: 0.00425 AC: 65 AN: 15290

Ashkenazi Jewish (ASJ) AF: 0.00202 AC: 7 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5176

South Asian (SAS) AF: 0.000415 AC: 2 AN: 4824

European-Finnish (FIN) AF: 0.00104 AC: 11 AN: 10612

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.00312 AC: 212 AN: 68022

Other (OTH) AF: 0.00331 AC: 7 AN: 2116

Alfa AF: 0.00276 Hom.: 0

Bravo AF: 0.00258

Asia WGS AF: 0.000577 AC: 2 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

Cataract 15 multiple types Benign:1

Jan 12, 2018

Illumina Laboratory Services, Illumina

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.74
CADD	Benign	5.1
DANN	Benign	0.80
PhyloP100		-0.15

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: rs137926387; hg19: chr12-56844573;