chr12-56451574-T-A

Variant names:

• chr12-56451574-T-A
• rs7953824
• NM_012064.4:c.607-109A>T

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BS1 BS2

The NM_012064.4(MIP):​c.607-109A>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000305 in 840,462 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: 𝑓 0.0012 (0 hom., cov: 33)
  • Exomes 𝑓: 0.00011 (0 hom.)
• Consequence: MIP NM_012064.4 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 2.02
• Publications: 5 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 -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.8).
• BS1: Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.00116 (177/152146) while in subpopulation AFR AF = 0.00414 (172/41530). AF 95% confidence interval is 0.00364. There are 0 homozygotes in GnomAd4. There are 95 alleles in the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check.
• BS2: High AC in GnomAd4 at 177 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
MIP	NM_012064.4	c.607-109A>T		intron_variant	Intron 3 of 3	ENST00000652304.1	NP_036196.1
MIP	XM_011538354.2	c.322-109A>T		intron_variant	Intron 5 of 5		XP_011536656.1
MIP	XM_017019306.2	c.250-109A>T		intron_variant	Intron 3 of 3		XP_016874795.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
MIP	ENST00000652304.1	c.607-109A>T		intron_variant	Intron 3 of 3		NM_012064.4	ENSP00000498622.1
ENSG00000285528	ENST00000648304.1	n.*231-109A>T		intron_variant	Intron 3 of 3			ENSP00000497190.1
MIP	ENST00000648442.1	n.740-109A>T		intron_variant	Intron 5 of 5
MIP	ENST00000650166.1	n.496-109A>T		intron_variant	Intron 4 of 4

Frequencies

GnomAD3 genomes AF: 0.00113 AC: 172 AN: 152028 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.00403

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000262

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.000479

GnomAD4 exome AF: 0.000115 AC: 79 AN: 688316 Hom.: 0 AF XY: 0.0000826 AC XY: 30 AN XY: 363330

African (AFR) AF: 0.00378 AC: 67 AN: 17708

American (AMR) AF: 0.000161 AC: 5 AN: 31008

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 18324

East Asian (EAS) AF: 0.00 AC: 0 AN: 35832

South Asian (SAS) AF: 0.00 AC: 0 AN: 62348

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 49690

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 2578

European-Non Finnish (NFE) AF: 0.00000229 AC: 1 AN: 436626

Other (OTH) AF: 0.000175 AC: 6 AN: 34202

GnomAD4 genome AF: 0.00116 AC: 177 AN: 152146 Hom.: 0 Cov.: 33 AF XY: 0.00128 AC XY: 95 AN XY: 74372

African (AFR) AF: 0.00414 AC: 172 AN: 41530

American (AMR) AF: 0.000262 AC: 4 AN: 15286

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3466

East Asian (EAS) AF: 0.00 AC: 0 AN: 5182

South Asian (SAS) AF: 0.00 AC: 0 AN: 4826

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10570

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 67978

Other (OTH) AF: 0.000474 AC: 1 AN: 2108

Alfa AF: 0.00 Hom.: 1457

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.80
CADD	Benign	0.61
DANN	Benign	0.23
PhyloP100		2.0

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

Other links and lift over

dbSNP: rs7953824; hg19: chr12-56845358;