rs146564314

Variant names:

• chr19-49168695-G-A
• rs146564314
• NM_017636.4:c.755G>A

Your query was ambiguous. Multiple possible variants found:

• chr19-49168695-G-A
• chr19-49168695-G-C
• chr19-49168695-G-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.755G>A​(p.Arg252His) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0055 in 1,608,374 control chromosomes in the GnomAD database, including 29 homozygotes. In-silico tool predicts a benign outcome for this variant. 12/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R252C) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.0042 (1 hom., cov: 30)
  • Exomes 𝑓: 0.0056 (28 hom.)
• Consequence: TRPM4 NM_017636.4 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:9
• Conservation: PhyloP100: 0.417
• Publications: 13 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=0.0078031123).
• BP6: Variant 19-49168695-G-A is Benign according to our data. Variant chr19-49168695-G-A is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 241182.
• BS2: High AC in GnomAd4 at 633 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.755G>A	p.Arg252His	missense	Exon 6 of 25	NP_060106.2
	TRPM4	NM_001321281.2		c.410G>A	p.Arg137His	missense	Exon 4 of 23	NP_001308210.1
	TRPM4	NM_001195227.2		c.755G>A	p.Arg252His	missense	Exon 6 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.755G>A	p.Arg252His	missense	Exon 6 of 25	ENSP00000252826.4	Q8TD43-1
	TRPM4	ENST00000427978.6	TSL:1	c.755G>A	p.Arg252His	missense	Exon 6 of 24	ENSP00000407492.1	Q8TD43-3
	TRPM4	ENST00000595519.5	TSL:1	n.*165G>A		non_coding_transcript_exon	Exon 4 of 23	ENSP00000469893.1	M0QYK7

Frequencies

GnomAD3 genomes AF: 0.00417 AC: 633 AN: 151962 Hom.: 1 Cov.: 30

Gnomad AFR AF: 0.00126

Gnomad AMI AF: 0.00219

Gnomad AMR AF: 0.00263

Gnomad ASJ AF: 0.0107

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.0110

Gnomad MID AF: 0.00316

Gnomad NFE AF: 0.00554

Gnomad OTH AF: 0.00336

GnomAD2 exomes AF: 0.00422 AC: 1000 AN: 237220 AF XY: 0.00424

Gnomad AFR exome AF: 0.00106

Gnomad AMR exome AF: 0.00126

Gnomad ASJ exome AF: 0.0111

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00875

Gnomad NFE exome AF: 0.00592

Gnomad OTH exome AF: 0.00520

GnomAD4 exome AF: 0.00564 AC: 8207 AN: 1456412 Hom.: 28 Cov.: 33 AF XY: 0.00554 AC XY: 4011 AN XY: 724162

African (AFR) AF: 0.00135 AC: 45 AN: 33434

American (AMR) AF: 0.00132 AC: 58 AN: 43970

Ashkenazi Jewish (ASJ) AF: 0.0113 AC: 293 AN: 25972

East Asian (EAS) AF: 0.0000253 AC: 1 AN: 39510

South Asian (SAS) AF: 0.0000702 AC: 6 AN: 85478

European-Finnish (FIN) AF: 0.00841 AC: 438 AN: 52078

Middle Eastern (MID) AF: 0.00104 AC: 6 AN: 5766

European-Non Finnish (NFE) AF: 0.00642 AC: 7124 AN: 1110050

Other (OTH) AF: 0.00392 AC: 236 AN: 60154

GnomAD4 genome AF: 0.00417 AC: 633 AN: 151962 Hom.: 1 Cov.: 30 AF XY: 0.00472 AC XY: 350 AN XY: 74216

African (AFR) AF: 0.00126 AC: 52 AN: 41368

American (AMR) AF: 0.00263 AC: 40 AN: 15210

Ashkenazi Jewish (ASJ) AF: 0.0107 AC: 37 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5184

South Asian (SAS) AF: 0.00 AC: 0 AN: 4822

European-Finnish (FIN) AF: 0.0110 AC: 117 AN: 10590

Middle Eastern (MID) AF: 0.00316 AC: 1 AN: 316

European-Non Finnish (NFE) AF: 0.00554 AC: 377 AN: 68006

Other (OTH) AF: 0.00336 AC: 7 AN: 2084

Alfa AF: 0.00533 Hom.: 9

Bravo AF: 0.00361

TwinsUK AF: 0.00782 AC: 29

ALSPAC AF: 0.00830 AC: 32

ESP6500AA AF: 0.000682 AC: 3

ESP6500EA AF: 0.00628 AC: 54

ExAC AF: 0.00378 AC: 458

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	Cardiomyopathy (1)
-	-	1	Cardiovascular phenotype (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.073
BayesDel_addAF	Benign	-0.43	T
BayesDel_noAF	Benign	-0.39
CADD	Benign	20
DANN	Pathogenic	1.0
DEOGEN2	Benign	0.36	T
Eigen	Benign	0.014
Eigen_PC	Benign	-0.15
FATHMM_MKL	Benign	0.12	N
LIST_S2	Benign	0.85	T
MetaRNN	Benign	0.0078	T
MetaSVM	Benign	-0.81	T
MutationAssessor	Uncertain	2.4	M
PhyloP100		0.42
PrimateAI	Benign	0.26	T
PROVEAN	Uncertain	-2.6	D
REVEL	Benign	0.16
Sift	Uncertain	0.0060	D
Sift4G	Uncertain	0.040	D
Polyphen		0.98	D
Vest4		0.33
MVP		0.86
MPC		0.41
ClinPred		0.018	T
GERP RS		2.4
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.13
gMVP		0.45
Mutation Taster		=256/44	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: rs146564314; hg19: chr19-49671952; COSMIC: COSV53267723; COSMIC: COSV53267723;