12-56453738-G-A

Variant names:

Variant summary

Our verdict is Benign. The variant received -19 ACMG points: 0P and 19B. BP4_ModerateBP6_Very_StrongBP7BS1BS2

The NM_012064.4(MIP):c.378C>T(p.Ser126Ser) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000254 in 1,613,746 control chromosomes in the GnomAD database, including 3 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

Frequency

Genomes: 𝑓 0.00018 ( 0 hom., cov: 32)

Exomes 𝑓: 0.00026 ( 3 hom. )

Consequence

MIP
NM_012064.4 synonymous

Scores

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:2

Conservation

PhyloP100: -1.42

Publications

2 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: 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

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 -19 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.39).

BP6

Variant 12-56453738-G-A is Benign according to our data. Variant chr12-56453738-G-A is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 309885.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BP7

Synonymous conserved (PhyloP=-1.41 with no splicing effect.

BS1

Variant frequency is greater than expected in population eas. GnomAd4 allele frequency = 0.000177 (27/152328) while in subpopulation EAS AF = 0.0029 (15/5178). AF 95% confidence interval is 0.00179. There are 0 homozygotes in GnomAd4. There are 11 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.

BS2

High AC in GnomAd4 at 27 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
MIP	NM_012064.4 link	c.378C>T	p.Ser126Ser	synonymous_variant	Exon 2 of 4	ENST00000652304.1	NP_036196.1	P30301
MIP	XM_011538354.2 link	c.93C>T	p.Ser31Ser	synonymous_variant	Exon 4 of 6		XP_011536656.1
MIP	XM_017019306.2 link	c.21C>T	p.Ser7Ser	synonymous_variant	Exon 2 of 4		XP_016874795.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
MIP	ENST00000652304.1 link	c.378C>T	p.Ser126Ser	synonymous_variant	Exon 2 of 4	NM_012064.4	ENSP00000498622.1	P30301
ENSG00000285528	ENST00000648304.1 link	n.*2C>T		non_coding_transcript_exon_variant	Exon 2 of 4		ENSP00000497190.1	A0A3B3IS89
ENSG00000285528	ENST00000648304.1 link	n.*2C>T		3_prime_UTR_variant	Exon 2 of 4		ENSP00000497190.1	A0A3B3IS89

Frequencies

GnomAD3 genomes

AF:

0.000177

AC:

AN:

152210

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.0000654

Gnomad ASJ

AF:

0.00288

Gnomad EAS

AF:

0.00289

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000147

Gnomad OTH

AF:

0.00

GnomAD2 exomes

AF:

0.000276

AC:

AN:

249684

AF XY:

0.000237

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.0000290

Gnomad ASJ exome

AF:

0.00319

Gnomad EAS exome

AF:

0.00169

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000355

Gnomad OTH exome

AF:

0.000165

GnomAD4 exome

AF:

0.000262

AC:

383

AN:

1461418

Hom.:

Cov.:

AF XY:

0.000239

AC XY:

174

AN XY:

726996

show subpopulations

African (AFR)

AF:

0.0000299

AC:

AN:

33476

American (AMR)

AF:

0.0000224

AC:

AN:

44646

Ashkenazi Jewish (ASJ)

AF:

0.00306

AC:

AN:

26118

East Asian (EAS)

AF:

0.00688

AC:

273

AN:

39698

South Asian (SAS)

AF:

0.00

AC:

AN:

86186

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53278

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5768

European-Non Finnish (NFE)

AF:

0.0000126

AC:

AN:

1111866

Other (OTH)

AF:

0.000232

AC:

AN:

60382

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.491

Heterozygous variant carriers

111

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Variant carriers

<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:

0.000177

AC:

AN:

152328

Hom.:

Cov.:

AF XY:

0.000148

AC XY:

AN XY:

74478

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

41576

American (AMR)

AF:

0.0000653

AC:

AN:

15306

Ashkenazi Jewish (ASJ)

AF:

0.00288

AC:

AN:

3472

East Asian (EAS)

AF:

0.00290

AC:

AN:

5178

South Asian (SAS)

AF:

0.00

AC:

AN:

4828

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10622

Middle Eastern (MID)

AF:

0.00

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.0000147

AC:

AN:

68026

Other (OTH)

AF:

0.00

AC:

AN:

2114

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.505

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Variant carriers

<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:

0.000229

Hom.:

Bravo

AF:

0.000151

Asia WGS

AF:

0.000289

AC:

AN:

3478

EpiCase

AF:

0.0000545

EpiControl

AF:

0.000119

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Cataract 15 multiple types

Benign:2

Jan 22, 2023

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Apr 27, 2017

Illumina Laboratory Services, Illumina

Significance:Likely 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). Publications were found based on this search. The evidence from the literature, in combination with allele frequency data from public databases where available, was sufficient to determine this variant is unlikely to cause disease. Therefore, this variant is classified as likely benign. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.39

CADD

Benign

3.9

(source)

DANN

Benign

0.82

PhyloP100

-1.4

Mutation Taster

=100/0

polymorphism

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.030

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

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over