12-49965105-G-A

Variant names:

• chr12-49965105-G-A
• rs41308104
• NM_001651.4:c.726G>A

Variant summary

Our verdict is Benign. The variant received -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BS1 BS2

The NM_001651.4(AQP5):​c.726G>A​(p.Thr242Thr) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0151 in 1,614,018 control chromosomes in the GnomAD database, including 232 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.012 (18 hom., cov: 32)
  • Exomes 𝑓: 0.015 (214 hom.)
• Consequence: AQP5 NM_001651.4 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -2.71
• Publications: 3 publications found

Genes affected

AQP5 (HGNC:638): (aquaporin 5) Aquaporin 5 (AQP5) is a water channel protein. Aquaporins are a family of small integral membrane proteins related to the major intrinsic protein (MIP or AQP0). Aquaporin 5 plays a role in the generation of saliva, tears and pulmonary secretions. AQP0, AQP2, AQP5, and AQP6 are closely related and all map to 12q13. [provided by RefSeq, Jul 2008]

AQP5-AS1 (HGNC:55474): (AQP5 and AQP2 antisense RNA 2)

LOC105369764 (HGNC:):

ACMG classification

Our verdict: Benign. The variant received -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.7).
• BP6: Variant 12-49965105-G-A is Benign according to our data. Variant chr12-49965105-G-A is described in ClinVar as Benign. ClinVar VariationId is 1562092.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=-2.71 with no splicing effect.
• BS1: Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.012 (1826/152308) while in subpopulation NFE AF = 0.0166 (1127/68026). AF 95% confidence interval is 0.0158. There are 18 homozygotes in GnomAd4. There are 892 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High AC in GnomAd4 at 1826 AD gene.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001651.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	AQP5	NM_001651.4	MANE Select	c.726G>A	p.Thr242Thr	synonymous	Exon 4 of 4	NP_001642.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	AQP5	ENST00000293599.7	TSL:1 MANE Select	c.726G>A	p.Thr242Thr	synonymous	Exon 4 of 4	ENSP00000293599.5
	AQP5	ENST00000553132.1	TSL:2	n.715G>A		non_coding_transcript_exon	Exon 2 of 2
	AQP5-AS1	ENST00000750790.1		n.301+578C>T		intron	N/A

Frequencies

GnomAD3 genomes AF: 0.0120 AC: 1828 AN: 152190 Hom.: 18 Cov.: 32

Gnomad AFR AF: 0.00347

Gnomad AMI AF: 0.00110

Gnomad AMR AF: 0.00746

Gnomad ASJ AF: 0.0510

Gnomad EAS AF: 0.000578

Gnomad SAS AF: 0.00207

Gnomad FIN AF: 0.0205

Gnomad MID AF: 0.00633

Gnomad NFE AF: 0.0166

Gnomad OTH AF: 0.0148

GnomAD2 exomes AF: 0.0126 AC: 3171 AN: 251084 AF XY: 0.0123

Gnomad AFR exome AF: 0.00277

Gnomad AMR exome AF: 0.00692

Gnomad ASJ exome AF: 0.0544

Gnomad EAS exome AF: 0.000707

Gnomad FIN exome AF: 0.0214

Gnomad NFE exome AF: 0.0151

Gnomad OTH exome AF: 0.0132

GnomAD4 exome AF: 0.0154 AC: 22538 AN: 1461710 Hom.: 214 Cov.: 33 AF XY: 0.0151 AC XY: 11010 AN XY: 727158

African (AFR) AF: 0.00251 AC: 84 AN: 33480

American (AMR) AF: 0.00711 AC: 318 AN: 44710

Ashkenazi Jewish (ASJ) AF: 0.0517 AC: 1350 AN: 26130

East Asian (EAS) AF: 0.000277 AC: 11 AN: 39700

South Asian (SAS) AF: 0.00284 AC: 245 AN: 86258

European-Finnish (FIN) AF: 0.0197 AC: 1053 AN: 53322

Middle Eastern (MID) AF: 0.0153 AC: 88 AN: 5768

European-Non Finnish (NFE) AF: 0.0166 AC: 18440 AN: 1111952

Other (OTH) AF: 0.0157 AC: 949 AN: 60390

GnomAD4 genome AF: 0.0120 AC: 1826 AN: 152308 Hom.: 18 Cov.: 32 AF XY: 0.0120 AC XY: 892 AN XY: 74480

African (AFR) AF: 0.00346 AC: 144 AN: 41568

American (AMR) AF: 0.00738 AC: 113 AN: 15302

Ashkenazi Jewish (ASJ) AF: 0.0510 AC: 177 AN: 3472

East Asian (EAS) AF: 0.000580 AC: 3 AN: 5176

South Asian (SAS) AF: 0.00207 AC: 10 AN: 4828

European-Finnish (FIN) AF: 0.0205 AC: 218 AN: 10614

Middle Eastern (MID) AF: 0.00680 AC: 2 AN: 294

European-Non Finnish (NFE) AF: 0.0166 AC: 1127 AN: 68026

Other (OTH) AF: 0.0147 AC: 31 AN: 2116

Alfa AF: 0.0146 Hom.: 13

Bravo AF: 0.0108

Asia WGS AF: 0.00346 AC: 12 AN: 3478

EpiCase AF: 0.0160

EpiControl AF: 0.0145

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

Jan 08, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.70
CADD	Benign	0.31
DANN	Benign	0.84
PhyloP100		-2.7
Mutation Taster		=100/0	polymorphism

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: rs41308104; hg19: chr12-50358888;