chr12-56454623-G-T

Variant names:

Variant summary

Our verdict is Benign. The variant received -18 ACMG points: 0P and 18B. BP4_ModerateBP6_Very_StrongBS1BS2

The NM_012064.4(MIP):c.-10C>A variant causes a 5 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.019 in 1,613,542 control chromosomes in the GnomAD database, including 382 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

Frequency

Genomes: 𝑓 0.016 ( 36 hom., cov: 32)

Exomes 𝑓: 0.019 ( 346 hom. )

Consequence

MIP
NM_012064.4 5_prime_UTR

Scores

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:3

Conservation

PhyloP100: 2.54

Publications

4 publications found

Variant links:

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: Ambry Genetics, Labcorp Genetics (formerly Invitae), G2P
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

MIP links:

ENSG00000285528 (HGNC:):

ENSG00000285528 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -18 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.42).

BP6

Variant 12-56454623-G-T is Benign according to our data. Variant chr12-56454623-G-T is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 309889.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BS1

Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.016 (2442/152308) while in subpopulation NFE AF = 0.0227 (1543/68026). AF 95% confidence interval is 0.0217. There are 36 homozygotes in GnomAd4. There are 1253 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.

BS2

High AC in GnomAd4 at 2442 AD gene.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_012064.4. 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.-10C>A		5_prime_UTR	Exon 1 of 4	NP_036196.1	P30301

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	Effect	Exon Rank	Protein	UniProt
MIP	ENST00000652304.1	MANE Select	c.-10C>A	5_prime_UTR	Exon 1 of 4	ENSP00000498622.1	P30301
MIP	ENST00000555551.1	TSL:1	n.317-868C>A	intron	N/A
ENSG00000285528	ENST00000648304.1		n.183-868C>A	intron	N/A	ENSP00000497190.1	A0A3B3IS89

Frequencies

GnomAD3 genomes

AF:

0.0160

AC:

2441

AN:

152190

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00367

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00609

Gnomad ASJ

AF:

0.0141

Gnomad EAS

AF:

0.000385

Gnomad SAS

AF:

0.0151

Gnomad FIN

AF:

0.0480

Gnomad MID

AF:

0.00316

Gnomad NFE

AF:

0.0227

Gnomad OTH

AF:

0.00908

GnomAD2 exomes

AF:

0.0169

AC:

4255

AN:

251184

AF XY:

0.0176

show subpopulations

Gnomad AFR exome

AF:

0.00295

Gnomad AMR exome

AF:

0.00408

Gnomad ASJ exome

AF:

0.0151

Gnomad EAS exome

AF:

0.000272

Gnomad FIN exome

AF:

0.0425

Gnomad NFE exome

AF:

0.0217

Gnomad OTH exome

AF:

0.0150

GnomAD4 exome

AF:

0.0193

AC:

28186

AN:

1461234

Hom.:

346

Cov.:

AF XY:

0.0194

AC XY:

14069

AN XY:

726930

show subpopulations

African (AFR)

AF:

0.00263

AC:

AN:

33454

American (AMR)

AF:

0.00389

AC:

174

AN:

44716

Ashkenazi Jewish (ASJ)

AF:

0.0129

AC:

337

AN:

26130

East Asian (EAS)

AF:

0.000101

AC:

AN:

39700

South Asian (SAS)

AF:

0.0153

AC:

1320

AN:

86210

European-Finnish (FIN)

AF:

0.0405

AC:

2161

AN:

53410

Middle Eastern (MID)

AF:

0.00891

AC:

AN:

5388

European-Non Finnish (NFE)

AF:

0.0207

AC:

23030

AN:

1111886

Other (OTH)

AF:

0.0170

AC:

1024

AN:

60340

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.466

Heterozygous variant carriers

1396

2792

4187

5583

6979

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

842

1684

2526

3368

4210

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.0160

AC:

2442

AN:

152308

Hom.:

Cov.:

AF XY:

0.0168

AC XY:

1253

AN XY:

74474

show subpopulations

African (AFR)

AF:

0.00366

AC:

152

AN:

41582

American (AMR)

AF:

0.00608

AC:

AN:

15298

Ashkenazi Jewish (ASJ)

AF:

0.0141

AC:

AN:

3470

East Asian (EAS)

AF:

0.000386

AC:

AN:

5182

South Asian (SAS)

AF:

0.0154

AC:

AN:

4820

European-Finnish (FIN)

AF:

0.0480

AC:

509

AN:

10610

Middle Eastern (MID)

AF:

0.00340

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.0227

AC:

1543

AN:

68026

Other (OTH)

AF:

0.00899

AC:

AN:

2114

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.496

Heterozygous variant carriers

113

226

339

452

565

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

102

136

170

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.0199

Hom.:

Bravo

AF:

0.0116

Asia WGS

AF:

0.00549

AC:

AN:

3478

ClinVar

ClinVar submissions

Significance:Benign/Likely benign

Revision:criteria provided, multiple submitters, no conflicts

View on ClinVar

Pathogenic

VUS

Benign

Condition

not provided (2)

Cataract 15 multiple types (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.42

CADD

Benign

(source)

DANN

Benign

0.89

PhyloP100

2.5

PromoterAI

-0.035

Neutral

(source)

Mutation Taster

=299/1

polymorphism (auto)

(source)

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over