chr12-56454697-T-C

Variant names:

• chr12-56454697-T-C
• rs2269348
• ENST00000555551.1:n.317-942A>G

Variant summary

Our verdict is Benign. The variant received -18 ACMG points: 0P and 18B. BP4_Moderate BP6_Very_Strong BA1

The ENST00000648304.1(ENSG00000285528):​n.183-942A>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.432 in 1,576,206 control chromosomes in the GnomAD database, including 151,506 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.37 (12330 hom., cov: 31)
  • Exomes 𝑓: 0.44 (139176 hom.)
• Consequence: ENSG00000285528 ENST00000648304.1 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 0.0510
• Publications: 11 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: Benign. The variant received -18 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.35).
• BP6: Variant 12-56454697-T-C is Benign according to our data. Variant chr12-56454697-T-C is described in ClinVar as Benign. ClinVar VariationId is 1231706.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.639 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: ENST00000648304.1. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	MIP	NM_012064.4	MANE Select	c.-84A>G		upstream_gene	N/A	NP_036196.1	P30301

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	MIP	ENST00000555551.1	TSL:1	n.317-942A>G		intron	N/A
	ENSG00000285528	ENST00000648304.1		n.183-942A>G		intron	N/A	ENSP00000497190.1	A0A3B3IS89
	MIP	ENST00000648442.1		n.494-942A>G		intron	N/A

Frequencies

GnomAD3 genomes AF: 0.375 AC: 57001 AN: 151930 Hom.: 12331 Cov.: 31

Gnomad AFR AF: 0.162

Gnomad AMI AF: 0.345

Gnomad AMR AF: 0.470

Gnomad ASJ AF: 0.487

Gnomad EAS AF: 0.658

Gnomad SAS AF: 0.402

Gnomad FIN AF: 0.413

Gnomad MID AF: 0.440

Gnomad NFE AF: 0.447

Gnomad OTH AF: 0.435

GnomAD4 exome AF: 0.438 AC: 623425 AN: 1424158 Hom.: 139176 AF XY: 0.437 AC XY: 309857 AN XY: 708330

African (AFR) AF: 0.150 AC: 4858 AN: 32418

American (AMR) AF: 0.568 AC: 24150 AN: 42522

Ashkenazi Jewish (ASJ) AF: 0.482 AC: 12009 AN: 24932

East Asian (EAS) AF: 0.594 AC: 23374 AN: 39338

South Asian (SAS) AF: 0.409 AC: 34028 AN: 83262

European-Finnish (FIN) AF: 0.428 AC: 22500 AN: 52512

Middle Eastern (MID) AF: 0.483 AC: 1962 AN: 4062

European-Non Finnish (NFE) AF: 0.437 AC: 474700 AN: 1086338

Other (OTH) AF: 0.440 AC: 25844 AN: 58774

GnomAD4 genome AF: 0.375 AC: 56988 AN: 152048 Hom.: 12330 Cov.: 31 AF XY: 0.377 AC XY: 28030 AN XY: 74324

African (AFR) AF: 0.161 AC: 6689 AN: 41506

American (AMR) AF: 0.470 AC: 7179 AN: 15272

Ashkenazi Jewish (ASJ) AF: 0.487 AC: 1689 AN: 3470

East Asian (EAS) AF: 0.658 AC: 3395 AN: 5160

South Asian (SAS) AF: 0.403 AC: 1937 AN: 4812

European-Finnish (FIN) AF: 0.413 AC: 4366 AN: 10564

Middle Eastern (MID) AF: 0.435 AC: 128 AN: 294

European-Non Finnish (NFE) AF: 0.447 AC: 30381 AN: 67948

Other (OTH) AF: 0.431 AC: 910 AN: 2112

Alfa AF: 0.423 Hom.: 1786

Bravo AF: 0.379

Asia WGS AF: 0.441 AC: 1538 AN: 3478

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	2	not provided (2)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.35
CADD	Benign	17
DANN	Benign	0.83
PhyloP100		0.051
PromoterAI		0.018	Neutral
Mutation Taster		=100/0	polymorphism (auto)

Splicing

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

MaxEntScan Visualizer can be used to analyze the impact of this mutation on the neighboring sequence.

Other links and lift over

dbSNP: rs2269348;

hg19: chr12-56848481;

COSMIC: COSV57788122;