rs150391806

Variant names:

• chr19-49211240-C-T
• rs150391806
• NM_017636.4:c.3611C>T

Variant summary

Our verdict is Benign. The variant received -9 ACMG points: 0P and 9B. BP4_Strong BP6 BS2

The NM_017636.4(TRPM4):​c.3611C>T​(p.Pro1204Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00315 in 1,589,480 control chromosomes in the GnomAD database, including 11 homozygotes. In-silico tool predicts a benign outcome for this variant. 13/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.0031 (1 hom., cov: 32)
  • Exomes 𝑓: 0.0032 (10 hom.)
• Consequence: TRPM4 NM_017636.4 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:10
• Conservation: PhyloP100: 2.03
• Publications: 23 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: Labcorp Genetics (formerly Invitae), G2P, 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 -9 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0052702427).
• BP6: Variant 19-49211240-C-T is Benign according to our data. Variant chr19-49211240-C-T is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 381692.
• BS2: High AC in GnomAd4 at 472 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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TRPM4	NM_017636.4	MANE Select	c.3611C>T	p.Pro1204Leu	missense	Exon 24 of 25	NP_060106.2
	TRPM4	NM_001321281.2		c.3266C>T	p.Pro1089Leu	missense	Exon 22 of 23	NP_001308210.1
	TRPM4	NM_001195227.2		c.3176C>T	p.Pro1059Leu	missense	Exon 23 of 24	NP_001182156.1	Q8TD43-3

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TRPM4	ENST00000252826.10	TSL:1 MANE Select	c.3611C>T	p.Pro1204Leu	missense	Exon 24 of 25	ENSP00000252826.4	Q8TD43-1
	TRPM4	ENST00000427978.6	TSL:1	c.3176C>T	p.Pro1059Leu	missense	Exon 23 of 24	ENSP00000407492.1	Q8TD43-3
	TRPM4	ENST00000595519.5	TSL:1	n.*3021C>T		non_coding_transcript_exon	Exon 22 of 23	ENSP00000469893.1	M0QYK7

Frequencies

GnomAD3 genomes AF: 0.00310 AC: 471 AN: 152122 Hom.: 1 Cov.: 32

Gnomad AFR AF: 0.000459

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00321

Gnomad ASJ AF: 0.00461

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000622

Gnomad FIN AF: 0.0101

Gnomad MID AF: 0.0158

Gnomad NFE AF: 0.00391

Gnomad OTH AF: 0.00287

GnomAD2 exomes AF: 0.00343 AC: 696 AN: 202944 AF XY: 0.00345

Gnomad AFR exome AF: 0.000325

Gnomad AMR exome AF: 0.00245

Gnomad ASJ exome AF: 0.00506

Gnomad EAS exome AF: 0.0000661

Gnomad FIN exome AF: 0.00988

Gnomad NFE exome AF: 0.00389

Gnomad OTH exome AF: 0.00384

GnomAD4 exome AF: 0.00316 AC: 4541 AN: 1437242 Hom.: 10 Cov.: 33 AF XY: 0.00312 AC XY: 2221 AN XY: 712962

African (AFR) AF: 0.000543 AC: 18 AN: 33128

American (AMR) AF: 0.00281 AC: 112 AN: 39816

Ashkenazi Jewish (ASJ) AF: 0.00528 AC: 135 AN: 25566

East Asian (EAS) AF: 0.00 AC: 0 AN: 38610

South Asian (SAS) AF: 0.00185 AC: 154 AN: 83192

European-Finnish (FIN) AF: 0.00846 AC: 431 AN: 50924

Middle Eastern (MID) AF: 0.00558 AC: 32 AN: 5736

European-Non Finnish (NFE) AF: 0.00311 AC: 3423 AN: 1100716

Other (OTH) AF: 0.00396 AC: 236 AN: 59554

GnomAD4 genome AF: 0.00310 AC: 472 AN: 152238 Hom.: 1 Cov.: 32 AF XY: 0.00331 AC XY: 246 AN XY: 74430

African (AFR) AF: 0.000457 AC: 19 AN: 41558

American (AMR) AF: 0.00321 AC: 49 AN: 15276

Ashkenazi Jewish (ASJ) AF: 0.00461 AC: 16 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5174

South Asian (SAS) AF: 0.000623 AC: 3 AN: 4818

European-Finnish (FIN) AF: 0.0101 AC: 107 AN: 10612

Middle Eastern (MID) AF: 0.0170 AC: 5 AN: 294

European-Non Finnish (NFE) AF: 0.00391 AC: 266 AN: 68008

Other (OTH) AF: 0.00331 AC: 7 AN: 2114

Alfa AF: 0.00353 Hom.: 4

Bravo AF: 0.00241

TwinsUK AF: 0.00189 AC: 7

ALSPAC AF: 0.00208 AC: 8

ESP6500AA AF: 0.000228 AC: 1

ESP6500EA AF: 0.00327 AC: 28

ExAC AF: 0.00268 AC: 324

Asia WGS AF: 0.00751 AC: 26 AN: 3478

ClinVar

ClinVar submissions

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
-	-	3	not specified (3)
-	1	2	Progressive familial heart block type IB (3)
-	-	2	not provided (2)
-	-	1	Cardiovascular phenotype (1)
-	-	1	Conduction disorder of the heart (1)
-	-	1	Family history of sudden cardiac death (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.079
BayesDel_addAF	Benign	-0.43	T
BayesDel_noAF	Benign	-0.39
CADD	Benign	19
DANN	Uncertain	0.98
DEOGEN2	Benign	0.13	T
Eigen	Benign	-0.63
Eigen_PC	Benign	-0.62
FATHMM_MKL	Benign	0.46	N
LIST_S2	Benign	0.55	T
MetaRNN	Benign	0.0053	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Uncertain	2.1	M
PhyloP100		2.0
PrimateAI	Uncertain	0.49	T
PROVEAN	Benign	-1.8	N
REVEL	Benign	0.066
Sift	Benign	0.21	T
Sift4G	Uncertain	0.014	D
Polyphen		0.64	P
Vest4		0.36
MVP		0.55
MPC		0.77
ClinPred		0.014	T
GERP RS		2.5
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.024
gMVP		0.32
Mutation Taster		=93/7	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.060		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: rs150391806; hg19: chr19-49714497; COSMIC: COSV53263347;