chr19-49167955-T-G

Variant names:

• chr19-49167955-T-G
• rs111783027
• NM_017636.4:c.306T>G

Variant summary

Our verdict is Benign. The variant received -17 ACMG points: 0P and 17B. BP4_Strong BP6_Very_Strong BP7 BS2

The NM_017636.4(TRPM4):​c.306T>G​(p.Val102Val) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00211 in 1,566,752 control chromosomes in the GnomAD database, including 51 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0066 (14 hom., cov: 32)
  • Exomes 𝑓: 0.0016 (37 hom.)
• Consequence: TRPM4 NM_017636.4 synonymous
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:10
• Conservation: PhyloP100: -0.436
• Publications: 0 publications found

Genes affected

TRPM4 (HGNC:17993): (transient receptor potential cation channel subfamily M member 4) The protein encoded by this gene is a calcium-activated nonselective ion channel that mediates transport of monovalent cations across membranes, thereby depolarizing the membrane. The activity of the encoded protein increases with increasing intracellular calcium concentration, but this channel does not transport calcium. [provided by RefSeq, Mar 2016]

TRPM4 Gene-Disease associations (from GenCC):

• erythrokeratodermia variabilis et progressiva 6

  Inheritance: AD Classification: STRONG, MODERATE, LIMITED Submitted by: G2P, Labcorp Genetics (formerly Invitae), Ambry Genetics
• progressive familial heart block type IB

  Inheritance: AD Classification: STRONG, MODERATE Submitted by: Genomics England PanelApp, Labcorp Genetics (formerly Invitae), Laboratory for Molecular Medicine
• erythrokeratodermia variabilis

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• progressive familial heart block

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• Brugada syndrome

  Inheritance: AD Classification: LIMITED, NO_KNOWN Submitted by: Genomics England PanelApp, ClinGen

ACMG classification

Our verdict: Benign. The variant received -17 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.5).
• BP6: Variant 19-49167955-T-G is Benign according to our data. Variant chr19-49167955-T-G is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 220960.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=-0.436 with no splicing effect.
• BS2: High AC in GnomAd4 at 987 AD gene.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_017636.4. 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
	TRPM4	NM_017636.4	MANE Select	c.306T>G	p.Val102Val	synonymous	Exon 4 of 25	NP_060106.2
	TRPM4	NM_001195227.2		c.306T>G	p.Val102Val	synonymous	Exon 4 of 24	NP_001182156.1
	TRPM4	NM_001321281.2		c.268-598T>G		intron	N/A	NP_001308210.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TRPM4	ENST00000252826.10	TSL:1 MANE Select	c.306T>G	p.Val102Val	synonymous	Exon 4 of 25	ENSP00000252826.4
	TRPM4	ENST00000427978.6	TSL:1	c.306T>G	p.Val102Val	synonymous	Exon 4 of 24	ENSP00000407492.1
	TRPM4	ENST00000595519.5	TSL:1	n.93-305T>G		intron	N/A	ENSP00000469893.1

Frequencies

GnomAD3 genomes AF: 0.00663 AC: 986 AN: 148680 Hom.: 14 Cov.: 32

Gnomad AFR AF: 0.00564

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00257

Gnomad ASJ AF: 0.0123

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.0109

Gnomad FIN AF: 0.0115

Gnomad MID AF: 0.00980

Gnomad NFE AF: 0.00755

Gnomad OTH AF: 0.00340

GnomAD2 exomes AF: 0.0000786 AC: 19 AN: 241648 AF XY: 0.0000767

Gnomad AFR exome AF: 0.000442

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.000210

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.000347

Gnomad NFE exome AF: 0.0000183

Gnomad OTH exome AF: 0.000169

GnomAD4 exome AF: 0.00163 AC: 2314 AN: 1417958 Hom.: 37 Cov.: 34 AF XY: 0.00187 AC XY: 1315 AN XY: 704414

African (AFR) AF: 0.00223 AC: 73 AN: 32770

American (AMR) AF: 0.000972 AC: 43 AN: 44216

Ashkenazi Jewish (ASJ) AF: 0.00507 AC: 126 AN: 24872

East Asian (EAS) AF: 0.00 AC: 0 AN: 39694

South Asian (SAS) AF: 0.00432 AC: 351 AN: 81194

European-Finnish (FIN) AF: 0.00530 AC: 267 AN: 50378

Middle Eastern (MID) AF: 0.00267 AC: 15 AN: 5616

European-Non Finnish (NFE) AF: 0.00124 AC: 1337 AN: 1080550

Other (OTH) AF: 0.00174 AC: 102 AN: 58668

GnomAD4 genome AF: 0.00663 AC: 987 AN: 148794 Hom.: 14 Cov.: 32 AF XY: 0.00684 AC XY: 497 AN XY: 72638

African (AFR) AF: 0.00565 AC: 231 AN: 40908

American (AMR) AF: 0.00257 AC: 39 AN: 15170

Ashkenazi Jewish (ASJ) AF: 0.0123 AC: 41 AN: 3324

East Asian (EAS) AF: 0.00 AC: 0 AN: 5172

South Asian (SAS) AF: 0.0109 AC: 50 AN: 4582

European-Finnish (FIN) AF: 0.0115 AC: 116 AN: 10104

Middle Eastern (MID) AF: 0.0106 AC: 3 AN: 284

European-Non Finnish (NFE) AF: 0.00755 AC: 500 AN: 66258

Other (OTH) AF: 0.00337 AC: 7 AN: 2080

Alfa AF: 0.0154 Hom.: 11

Bravo AF: 0.0145

ClinVar

ClinVar submissions as Germline

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	4	not specified (4)
-	-	2	not provided (2)
-	-	2	Progressive familial heart block type IB (2)
-	-	1	Cardiovascular phenotype (1)
-	-	1	TRPM4-related disorder (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.50
CADD	Benign	6.4
DANN	Benign	0.70
PhyloP100		-0.44
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Mutation Taster		=99/1	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs111783027; hg19: chr19-49671212; COSMIC: COSV53269460; COSMIC: COSV53269460;