rs61759527

Positions:

• chr12-56454623-G-T

Variant summary

Our verdict is Benign. Variant got -18 ACMG points: 0P and 18B. BP4_Moderate BP6_Very_Strong BS1 BS2

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
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: 2.54

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 Benign. Variant got -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 [Likely_benign]. Clinvar id is 309889.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr12-56454623-G-T is described in Lovd as [Likely_benign].
• 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 male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.
• BS2: High AC in GnomAd4 at 2442 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
MIP	NM_012064.4	c.-10C>A		5_prime_UTR_variant	1/4	ENST00000652304.1	NP_036196.1
MIP	XM_011538354.2	c.76-868C>A		intron_variant			XP_011536656.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
MIP	ENST00000652304.1	c.-10C>A		5_prime_UTR_variant	1/4		NM_012064.4	ENSP00000498622	P1
MIP	ENST00000555551.1	n.317-868C>A		intron_variant, non_coding_transcript_variant		1
MIP	ENST00000648442.1	n.494-868C>A		intron_variant, non_coding_transcript_variant
MIP	ENST00000650166.1	n.250-868C>A		intron_variant, non_coding_transcript_variant

Frequencies

GnomAD3 genomes AF: 0.0160 AC: 2441 AN: 152190 Hom.: 36 Cov.: 32

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

GnomAD3 exomes AF: 0.0169 AC: 4255 AN: 251184 Hom.: 48 AF XY: 0.0176 AC XY: 2395 AN XY: 135762

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 SAS exome AF: 0.0142

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.: 33 AF XY: 0.0194 AC XY: 14069 AN XY: 726930

Gnomad4 AFR exome AF: 0.00263

Gnomad4 AMR exome AF: 0.00389

Gnomad4 ASJ exome AF: 0.0129

Gnomad4 EAS exome AF: 0.000101

Gnomad4 SAS exome AF: 0.0153

Gnomad4 FIN exome AF: 0.0405

Gnomad4 NFE exome AF: 0.0207

Gnomad4 OTH exome AF: 0.0170

GnomAD4 genome AF: 0.0160 AC: 2442 AN: 152308 Hom.: 36 Cov.: 32 AF XY: 0.0168 AC XY: 1253 AN XY: 74474

Gnomad4 AFR AF: 0.00366

Gnomad4 AMR AF: 0.00608

Gnomad4 ASJ AF: 0.0141

Gnomad4 EAS AF: 0.000386

Gnomad4 SAS AF: 0.0154

Gnomad4 FIN AF: 0.0480

Gnomad4 NFE AF: 0.0227

Gnomad4 OTH AF: 0.00899

Alfa AF: 0.0183 Hom.: 14

Bravo AF: 0.0116

Asia WGS AF: 0.00549 AC: 19 AN: 3478

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Likely benign, criteria provided, single submitter	clinical testing	GeneDx	Jul 31, 2018	- -
Likely benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -

Cataract 15 multiple types Benign:1

Benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jan 12, 2018

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	-0.42
CADD	Benign	15
DANN	Benign	0.89

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

LitVar

Other links and lift over

dbSNP: rs61759527; hg19: chr12-56848407;