9-74827700-C-T

Variant names:

• chr9-74827700-C-T
• rs7045949
• NM_017662.5:c.841+78G>A

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_017662.5(TRPM6):​c.841+78G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.584 in 1,483,244 control chromosomes in the GnomAD database, including 255,676 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.60 (27311 hom., cov: 29)
  • Exomes 𝑓: 0.58 (228365 hom.)
• Consequence: TRPM6 NM_017662.5 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -2.91

Genes affected

TRPM6 (HGNC:17995): (transient receptor potential cation channel subfamily M member 6) This gene is predominantly expressed in the kidney and colon, and encodes a protein containing an ion channel domain and a protein kinase domain. It is crucial for magnesium homeostasis, and plays an essential role in epithelial magnesium transport and in the active magnesium absorption in the gut and kidney. Mutations in this gene are associated with hypomagnesemia with secondary hypocalcemia. Alternatively spliced transcript variants encoding different isoforms have been noted for this gene. [provided by RefSeq, Apr 2010]

ACMG classification

Our verdict: Benign. The variant received -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.96).
• BP6: Variant 9-74827700-C-T is Benign according to our data. Variant chr9-74827700-C-T is described in ClinVar as [Benign]. Clinvar id is 1236618.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr9-74827700-C-T is described in Lovd as [Benign].
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.774 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
TRPM6	NM_017662.5	c.841+78G>A		intron_variant	Intron 7 of 38	ENST00000360774.6	NP_060132.3
TRPM6	NM_001177310.2	c.826+78G>A		intron_variant	Intron 7 of 38		NP_001170781.1
TRPM6	NM_001177311.2	c.826+78G>A		intron_variant	Intron 7 of 38		NP_001170782.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
TRPM6	ENST00000360774.6	c.841+78G>A		intron_variant	Intron 7 of 38	1	NM_017662.5	ENSP00000354006.1

Frequencies

GnomAD3 genomes AF: 0.597 AC: 90327 AN: 151362 Hom.: 27255 Cov.: 29

Gnomad AFR AF: 0.648

Gnomad AMI AF: 0.620

Gnomad AMR AF: 0.582

Gnomad ASJ AF: 0.485

Gnomad EAS AF: 0.795

Gnomad SAS AF: 0.706

Gnomad FIN AF: 0.539

Gnomad MID AF: 0.443

Gnomad NFE AF: 0.563

Gnomad OTH AF: 0.554

GnomAD2 exomes AF: 0.614 AC: 152526 AN: 248538 AF XY: 0.613

Gnomad AFR exome AF: 0.654

Gnomad AMR exome AF: 0.659

Gnomad ASJ exome AF: 0.481

Gnomad EAS exome AF: 0.815

Gnomad FIN exome AF: 0.540

Gnomad NFE exome AF: 0.563

Gnomad OTH exome AF: 0.578

GnomAD4 exome AF: 0.583 AC: 775842 AN: 1331764 Hom.: 228365 Cov.: 20 AF XY: 0.585 AC XY: 391806 AN XY: 669286

Gnomad4 AFR exome AF: 0.646 AC: 19932 AN: 30858

Gnomad4 AMR exome AF: 0.652 AC: 28968 AN: 44452

Gnomad4 ASJ exome AF: 0.488 AC: 12380 AN: 25370

Gnomad4 EAS exome AF: 0.793 AC: 30999 AN: 39090

Gnomad4 SAS exome AF: 0.706 AC: 59044 AN: 83646

Gnomad4 FIN exome AF: 0.550 AC: 29361 AN: 53338

Gnomad4 NFE exome AF: 0.564 AC: 559932 AN: 993278

Gnomad4 Remaining exome AF: 0.578 AC: 32471 AN: 56212

GnomAD4 genome AF: 0.597 AC: 90450 AN: 151480 Hom.: 27311 Cov.: 29 AF XY: 0.598 AC XY: 44238 AN XY: 73976

Gnomad4 AFR AF: 0.649 AC: 0.648641 AN: 0.648641

Gnomad4 AMR AF: 0.582 AC: 0.582448 AN: 0.582448

Gnomad4 ASJ AF: 0.485 AC: 0.484735 AN: 0.484735

Gnomad4 EAS AF: 0.795 AC: 0.79476 AN: 0.79476

Gnomad4 SAS AF: 0.707 AC: 0.706681 AN: 0.706681

Gnomad4 FIN AF: 0.539 AC: 0.538923 AN: 0.538923

Gnomad4 NFE AF: 0.563 AC: 0.562876 AN: 0.562876

Gnomad4 OTH AF: 0.560 AC: 0.559524 AN: 0.559524

Alfa AF: 0.572 Hom.: 103733

Bravo AF: 0.602

Asia WGS AF: 0.723 AC: 2514 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Aug 20, 2019

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.96
CADD	Benign	0.13
DANN	Benign	0.38
Mutation Taster		=100/0	polymorphism (auto)

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: rs7045949; hg19: chr9-77442616; COSMIC: COSV62507537;