12-56450041-C-CAA

Position:

• chr12-56450041-C-CAA

Variant summary

Our verdict is Likely benign. Variant got -5 ACMG points: 0P and 5B. BS1_Supporting BS2

The NM_012064.4(MIP):​c.*1238_*1239insTT variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. Variant has been reported in ClinVar as Uncertain significance (★★).

• Frequency:
  • Genomes: 𝑓 0.019 (29 hom., cov: 0)
  • Failed GnomAD Quality Control
• Consequence: MIP NM_012064.4 3_prime_UTR
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:2
• Conservation: PhyloP100: 0.669

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 Likely_benign. Variant got -5 ACMG points.

• BS1: Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.0189 (2764/146482) while in subpopulation NFE AF= 0.0264 (1754/66556). AF 95% confidence interval is 0.0253. There are 29 homozygotes in gnomad4. There are 1364 alleles in male gnomad4 subpopulation. Median coverage is 0. This position pass quality control queck. Existence of Clinvar submissions makes me limit the strength of this signal to Supporting
• BS2: High AC in GnomAd4 at 2764 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
MIP	NM_012064.4	c.*1238_*1239insTT		3_prime_UTR_variant	4/4	ENST00000652304.1	NP_036196.1
MIP	XM_011538354.2	c.*1238_*1239insTT		3_prime_UTR_variant	6/6		XP_011536656.1
MIP	XM_017019306.2	c.*1238_*1239insTT		3_prime_UTR_variant	4/4		XP_016874795.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
MIP	ENST00000652304.1	c.*1238_*1239insTT		3_prime_UTR_variant	4/4		NM_012064.4	ENSP00000498622	P1

Frequencies

GnomAD3 genomes AF: 0.0188 AC: 2759 AN: 146408 Hom.: 29 Cov.: 0

Gnomad AFR AF: 0.00754

Gnomad AMI AF: 0.00551

Gnomad AMR AF: 0.0186

Gnomad ASJ AF: 0.0305

Gnomad EAS AF: 0.00354

Gnomad SAS AF: 0.00816

Gnomad FIN AF: 0.0240

Gnomad MID AF: 0.0130

Gnomad NFE AF: 0.0263

Gnomad OTH AF: 0.0244

GnomAD4 exome Data not reliable, filtered out with message: AC0 AC: 0 AN: 0 Hom.: 0 Cov.: 0 AC XY: 0 AN XY: 0

GnomAD4 genome AF: 0.0189 AC: 2764 AN: 146482 Hom.: 29 Cov.: 0 AF XY: 0.0192 AC XY: 1364 AN XY: 71062

Gnomad4 AFR AF: 0.00758

Gnomad4 AMR AF: 0.0186

Gnomad4 ASJ AF: 0.0305

Gnomad4 EAS AF: 0.00355

Gnomad4 SAS AF: 0.00862

Gnomad4 FIN AF: 0.0240

Gnomad4 NFE AF: 0.0264

Gnomad4 OTH AF: 0.0246

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Cataract Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jun 14, 2016

- -

not provided Uncertain:1

Uncertain significance, criteria provided, single submitter

not provided

Breakthrough Genomics, Breakthrough Genomics

-

- -

Computational scores

Source: dbNSFP v4.3

Splicing

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

Publications

LitVar

Other links and lift over

dbSNP: rs111463603; hg19: chr12-56843825;