chr19-49196848-C-T

Variant names:

• chr19-49196848-C-T
• rs144544237
• NM_017636.4:c.2619C>T

Variant summary

Our verdict is Benign. The variant received -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BS1 BS2

The NM_017636.4(TRPM4):​c.2619C>T​(p.Thr873Thr) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00141 in 1,587,464 control chromosomes in the GnomAD database, including 30 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0073 (18 hom., cov: 32)
  • Exomes 𝑓: 0.00078 (12 hom.)
• Consequence: TRPM4 NM_017636.4 synonymous
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:7
• Conservation: PhyloP100: -0.0470
• 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: 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 -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.6).
• BP6: Variant 19-49196848-C-T is Benign according to our data. Variant chr19-49196848-C-T is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 468936.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=-0.047 with no splicing effect.
• BS1: Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.00735 (1119/152308) while in subpopulation AFR AF = 0.0255 (1062/41578). AF 95% confidence interval is 0.0243. There are 18 homozygotes in GnomAd4. There are 517 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High AC in GnomAd4 at 1119 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.2619C>T	p.Thr873Thr	synonymous	Exon 17 of 25	NP_060106.2
	TRPM4	NM_001321281.2		c.2274C>T	p.Thr758Thr	synonymous	Exon 15 of 23	NP_001308210.1
	TRPM4	NM_001321283.2		c.2097C>T	p.Thr699Thr	synonymous	Exon 15 of 23	NP_001308212.1	Q8TD43-2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TRPM4	ENST00000252826.10	TSL:1 MANE Select	c.2619C>T	p.Thr873Thr	synonymous	Exon 17 of 25	ENSP00000252826.4	Q8TD43-1
	TRPM4	ENST00000427978.6	TSL:1	c.2211-3452C>T		intron	N/A	ENSP00000407492.1	Q8TD43-3
	TRPM4	ENST00000595519.5	TSL:1	n.*2029C>T		non_coding_transcript_exon	Exon 15 of 23	ENSP00000469893.1	M0QYK7

Frequencies

GnomAD3 genomes AF: 0.00733 AC: 1115 AN: 152190 Hom.: 18 Cov.: 32

Gnomad AFR AF: 0.0255

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00216

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000414

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000735

Gnomad OTH AF: 0.00813

GnomAD2 exomes AF: 0.00175 AC: 365 AN: 208088 AF XY: 0.00137

Gnomad AFR exome AF: 0.0258

Gnomad AMR exome AF: 0.00114

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.0000615

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000421

Gnomad OTH exome AF: 0.00112

GnomAD4 exome AF: 0.000776 AC: 1113 AN: 1435156 Hom.: 12 Cov.: 32 AF XY: 0.000667 AC XY: 476 AN XY: 713432

African (AFR) AF: 0.0270 AC: 893 AN: 33096

American (AMR) AF: 0.00120 AC: 52 AN: 43382

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25852

East Asian (EAS) AF: 0.00 AC: 0 AN: 38984

South Asian (SAS) AF: 0.0000954 AC: 8 AN: 83844

European-Finnish (FIN) AF: 0.0000784 AC: 3 AN: 38252

Middle Eastern (MID) AF: 0.000966 AC: 5 AN: 5174

European-Non Finnish (NFE) AF: 0.0000388 AC: 43 AN: 1106906

Other (OTH) AF: 0.00183 AC: 109 AN: 59666

GnomAD4 genome AF: 0.00735 AC: 1119 AN: 152308 Hom.: 18 Cov.: 32 AF XY: 0.00694 AC XY: 517 AN XY: 74486

African (AFR) AF: 0.0255 AC: 1062 AN: 41578

American (AMR) AF: 0.00216 AC: 33 AN: 15302

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3466

East Asian (EAS) AF: 0.00 AC: 0 AN: 5180

South Asian (SAS) AF: 0.000415 AC: 2 AN: 4824

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10620

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

European-Non Finnish (NFE) AF: 0.0000735 AC: 5 AN: 68018

Other (OTH) AF: 0.00804 AC: 17 AN: 2114

Alfa AF: 0.00439 Hom.: 2

Bravo AF: 0.00815

Asia WGS AF: 0.000577 AC: 2 AN: 3478

ClinVar

ClinVar submissions

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

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

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.60
CADD	Benign	9.7
DANN	Benign	0.67
PhyloP100		-0.047
Mutation Taster		=100/0	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: rs144544237; hg19: chr19-49700105;