chr19-49171589-C-T

Variant names:

• chr19-49171589-C-T
• rs141997826
• NM_017636.4:c.870C>T

Variant summary

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

The NM_001321282.2(TRPM4):​c.-684C>T variant causes a 5 prime UTR premature start codon gain change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00389 in 1,613,980 control chromosomes in the GnomAD database, including 22 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.0037 (7 hom., cov: 32)
  • Exomes 𝑓: 0.0039 (15 hom.)
• Consequence: TRPM4 NM_001321282.2 5_prime_UTR_premature_start_codon_gain
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:9
• Conservation: PhyloP100: -2.22
• Publications: 1 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 (BayesDel_noAF=-0.73).
• BP6: Variant 19-49171589-C-T is Benign according to our data. Variant chr19-49171589-C-T is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 386319.
• BS2: High AC in GnomAd4 at 560 AD gene.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001321282.2. 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.870C>T	p.Asn290Asn	synonymous	Exon 8 of 25	NP_060106.2
	TRPM4	NM_001321282.2		c.-684C>T		5_prime_UTR_premature_start_codon_gain	Exon 7 of 24	NP_001308211.1
	TRPM4	NM_001321281.2		c.525C>T	p.Asn175Asn	synonymous	Exon 6 of 23	NP_001308210.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TRPM4	ENST00000252826.10	TSL:1 MANE Select	c.870C>T	p.Asn290Asn	synonymous	Exon 8 of 25	ENSP00000252826.4	Q8TD43-1
	TRPM4	ENST00000427978.6	TSL:1	c.870C>T	p.Asn290Asn	synonymous	Exon 8 of 24	ENSP00000407492.1	Q8TD43-3
	TRPM4	ENST00000595519.5	TSL:1	n.*280C>T		non_coding_transcript_exon	Exon 6 of 23	ENSP00000469893.1	M0QYK7

Frequencies

GnomAD3 genomes AF: 0.00368 AC: 560 AN: 152074 Hom.: 7 Cov.: 32

Gnomad AFR AF: 0.000556

Gnomad AMI AF: 0.0450

Gnomad AMR AF: 0.00236

Gnomad ASJ AF: 0.00202

Gnomad EAS AF: 0.000193

Gnomad SAS AF: 0.000414

Gnomad FIN AF: 0.00680

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00543

Gnomad OTH AF: 0.00431

GnomAD2 exomes AF: 0.00313 AC: 785 AN: 250494 AF XY: 0.00327

Gnomad AFR exome AF: 0.000376

Gnomad AMR exome AF: 0.00127

Gnomad ASJ exome AF: 0.00249

Gnomad EAS exome AF: 0.000109

Gnomad FIN exome AF: 0.00693

Gnomad NFE exome AF: 0.00466

Gnomad OTH exome AF: 0.00343

GnomAD4 exome AF: 0.00391 AC: 5714 AN: 1461788 Hom.: 15 Cov.: 32 AF XY: 0.00378 AC XY: 2748 AN XY: 727208

African (AFR) AF: 0.000478 AC: 16 AN: 33480

American (AMR) AF: 0.00121 AC: 54 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.00214 AC: 56 AN: 26136

East Asian (EAS) AF: 0.0000756 AC: 3 AN: 39700

South Asian (SAS) AF: 0.000255 AC: 22 AN: 86258

European-Finnish (FIN) AF: 0.00743 AC: 396 AN: 53330

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5764

European-Non Finnish (NFE) AF: 0.00445 AC: 4950 AN: 1112004

Other (OTH) AF: 0.00359 AC: 217 AN: 60392

GnomAD4 genome AF: 0.00368 AC: 560 AN: 152192 Hom.: 7 Cov.: 32 AF XY: 0.00364 AC XY: 271 AN XY: 74400

African (AFR) AF: 0.000554 AC: 23 AN: 41524

American (AMR) AF: 0.00236 AC: 36 AN: 15282

Ashkenazi Jewish (ASJ) AF: 0.00202 AC: 7 AN: 3470

East Asian (EAS) AF: 0.000193 AC: 1 AN: 5176

South Asian (SAS) AF: 0.000207 AC: 1 AN: 4828

European-Finnish (FIN) AF: 0.00680 AC: 72 AN: 10596

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.00544 AC: 370 AN: 67998

Other (OTH) AF: 0.00426 AC: 9 AN: 2112

Alfa AF: 0.00451 Hom.: 0

Bravo AF: 0.00328

Asia WGS AF: 0.000577 AC: 2 AN: 3478

EpiCase AF: 0.00414

EpiControl AF: 0.00409

ClinVar

ClinVar submissions

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
-	-	4	not specified (4)
-	-	3	not provided (3)
-	1	1	Progressive familial heart block type IB (2)
-	-	1	Cardiovascular phenotype (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.73
CADD	Benign	1.1
DANN	Benign	0.48
PhyloP100		-2.2
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.8
Mutation Taster		=100/0	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.10		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: rs141997826; hg19: chr19-49674846; COSMIC: COSV99418999; COSMIC: COSV99418999;