19-16519686-G-A

Variant names:

• chr19-16519686-G-A
• rs745937321
• NM_006387.6:c.2492C>T

Variant summary

Our verdict is Likely benign. The variant received -4 ACMG points: 0P and 4B. BS2

The NM_006387.6(CHERP):​c.2492C>T​(p.Ala831Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000341 in 1,613,786 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.000046 (0 hom., cov: 32)
  • Exomes 𝑓: 0.000033 (0 hom.)
• Consequence: CHERP NM_006387.6 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 2.75
• Publications: 0 publications found

Genes affected

CHERP (HGNC:16930): (calcium homeostasis endoplasmic reticulum protein) Enables transmembrane transporter binding activity. Involved in positive regulation of calcineurin-NFAT signaling cascade and release of sequestered calcium ion into cytosol. Acts upstream of or within cellular calcium ion homeostasis and negative regulation of cell population proliferation. Located in perinuclear region of cytoplasm. [provided by Alliance of Genome Resources, Apr 2022]

C19orf44 (HGNC:26141): (chromosome 19 open reading frame 44)

C19orf44 Gene-Disease associations (from GenCC):

• inherited retinal dystrophy

  Inheritance: AR Classification: LIMITED Submitted by: Ambry Genetics

ENSG00000141979 (HGNC:):

ACMG classification

Our verdict: Likely_benign. The variant received -4 ACMG points.

• BS2: High AC in GnomAd4 at 7 AD gene.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_006387.6. 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
	CHERP	NM_006387.6	MANE Select	c.2492C>T	p.Ala831Val	missense	Exon 16 of 17	NP_006378.3
	C19orf44	NM_032207.4	MANE Select	c.*41-408G>A		intron	N/A	NP_115583.1	Q9H6X5-1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CHERP	ENST00000546361.7	TSL:1 MANE Select	c.2492C>T	p.Ala831Val	missense	Exon 16 of 17	ENSP00000439856.2	Q8IWX8
	C19orf44	ENST00000221671.8	TSL:2 MANE Select	c.*41-408G>A		intron	N/A	ENSP00000221671.2	Q9H6X5-1
	ENSG00000141979	ENST00000409035.1	TSL:2	n.*194-334C>T		intron	N/A	ENSP00000386951.2	B8ZZF3

Frequencies

GnomAD3 genomes AF: 0.0000460 AC: 7 AN: 152168 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00104

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000294

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.0000761 AC: 19 AN: 249552 AF XY: 0.0000886

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.0000869

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00000883

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000328 AC: 48 AN: 1461618 Hom.: 0 Cov.: 31 AF XY: 0.0000454 AC XY: 33 AN XY: 727102

African (AFR) AF: 0.0000896 AC: 3 AN: 33480

American (AMR) AF: 0.0000671 AC: 3 AN: 44722

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26130

East Asian (EAS) AF: 0.00 AC: 0 AN: 39698

South Asian (SAS) AF: 0.000383 AC: 33 AN: 86250

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53352

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5768

European-Non Finnish (NFE) AF: 0.00000540 AC: 6 AN: 1111850

Other (OTH) AF: 0.0000497 AC: 3 AN: 60368

GnomAD4 genome AF: 0.0000460 AC: 7 AN: 152168 Hom.: 0 Cov.: 32 AF XY: 0.0000673 AC XY: 5 AN XY: 74340

African (AFR) AF: 0.00 AC: 0 AN: 41450

American (AMR) AF: 0.00 AC: 0 AN: 15272

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5194

South Asian (SAS) AF: 0.00104 AC: 5 AN: 4822

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10612

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 316

European-Non Finnish (NFE) AF: 0.0000294 AC: 2 AN: 68026

Other (OTH) AF: 0.00 AC: 0 AN: 2092

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.00000756

ExAC AF: 0.000107 AC: 13

EpiCase AF: 0.00

EpiControl AF: 0.0000593

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.070
BayesDel_addAF	Benign	-0.38	T
BayesDel_noAF	Benign	-0.46
CADD	Pathogenic	30
DANN	Uncertain	1.0
DEOGEN2	Benign	0.068	T
Eigen	Uncertain	0.23
Eigen_PC	Uncertain	0.30
FATHMM_MKL	Uncertain	0.92	D
LIST_S2	Benign	0.80	T
M_CAP	Benign	0.015	T
MetaRNN	Benign	0.072	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	1.2	L
PhyloP100		2.8
PrimateAI	Uncertain	0.57	T
PROVEAN	Benign	-1.4	N
REVEL	Benign	0.092
Sift	Uncertain	0.010	D
Sift4G	Benign	0.20	T
Polyphen		0.84	P
Vest4		0.082
MutPred		0.068		Loss of glycosylation at S830 (P = 0.2249)
MVP		0.41
MPC		0.81
ClinPred		0.12	T
GERP RS		3.9
Varity_R		0.14
gMVP		0.62
Mutation Taster		=93/7	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.33		Details are displayed if max score is > 0.2
DS_AG_spliceai		0.33		Position offset: -22

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs745937321; hg19: chr19-16630497; COSMIC: COSV52222414; COSMIC: COSV52222414;