dbSNP rs375718104: TMCC2:p.Arg199His (chr1-205241893-G-A) – ACMG Classification: Likely_benign (-1 pts)

Variant summary

Our verdict is Likely benign. The variant received -1 ACMG points: 0P and 1B. BP4

The NM_014858.4(TMCC2):c.596G>A(p.Arg199His) variant causes a missense change. The variant allele was found at a frequency of 0.00016 in 1,607,400 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 0.000079 ( 0 hom., cov: 32)

Exomes 𝑓: 0.00017 ( 0 hom. )

Consequence

TMCC2
NM_014858.4 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 6.25

Publications

2 publications found

Variant links:

Genes affected

TMCC2 (HGNC:24239): (transmembrane and coiled-coil domain family 2) Involved in amyloid precursor protein metabolic process. Located in endoplasmic reticulum. [provided by Alliance of Genome Resources, Apr 2022]

TMCC2 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Likely_benign. The variant received -1 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.3102375).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
TMCC2	NM_014858.4 link	c.596G>A	p.Arg199His	missense_variant	Exon 2 of 5	ENST00000358024.8	NP_055673.2	O75069-1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	UniProt
TMCC2	ENST00000358024.8 link	c.596G>A	p.Arg199His	missense_variant	Exon 2 of 5	1	NM_014858.4	ENSP00000350718.3	O75069-1
TMCC2	ENST00000545499.5 link	c.362G>A	p.Arg121His	missense_variant	Exon 2 of 5	2		ENSP00000437943.1	O75069-2
TMCC2	ENST00000495538.5 link	n.827G>A		non_coding_transcript_exon_variant	Exon 2 of 5	5

Frequencies

GnomAD3 genomes

AF:

0.0000789

AC:

AN:

152116

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000241

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000162

Gnomad OTH

AF:

0.00

GnomAD2 exomes

AF:

0.0000695

AC:

AN:

230106

AF XY:

0.0000711

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.000119

Gnomad OTH exome

AF:

0.000177

GnomAD4 exome

AF:

0.000168

AC:

245

AN:

1455284

Hom.:

Cov.:

AF XY:

0.000167

AC XY:

121

AN XY:

723770

show subpopulations

African (AFR)

AF:

0.0000300

AC:

AN:

33378

American (AMR)

AF:

0.00

AC:

AN:

44248

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

25978

East Asian (EAS)

AF:

0.0000506

AC:

AN:

39510

South Asian (SAS)

AF:

0.000187

AC:

AN:

85592

European-Finnish (FIN)

AF:

0.00

AC:

AN:

50854

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5154

European-Non Finnish (NFE)

AF:

0.000195

AC:

216

AN:

1110534

Other (OTH)

AF:

0.000167

AC:

AN:

60036

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.490

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Variant carriers

100

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.0000789

AC:

AN:

152116

Hom.:

Cov.:

AF XY:

0.0000538

AC XY:

AN XY:

74302

show subpopulations

African (AFR)

AF:

0.0000241

AC:

AN:

41422

American (AMR)

AF:

0.00

AC:

AN:

15286

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3470

East Asian (EAS)

AF:

0.00

AC:

AN:

5174

South Asian (SAS)

AF:

0.00

AC:

AN:

4824

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10606

Middle Eastern (MID)

AF:

0.00

AC:

AN:

316

European-Non Finnish (NFE)

AF:

0.000162

AC:

AN:

68018

Other (OTH)

AF:

0.00

AC:

AN:

2088

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.517

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.000180

Hom.:

Bravo

AF:

0.0000945

ESP6500AA

AF:

0.000232

AC:

ESP6500EA

AF:

0.000118

AC:

ExAC

AF:

0.0000830

AC:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Feb 15, 2023

Ambry Genetics

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

The c.596G>A (p.R199H) alteration is located in exon 2 (coding exon 2) of the TMCC2 gene. This alteration results from a G to A substitution at nucleotide position 596, causing the arginine (R) at amino acid position 199 to be replaced by a histidine (H). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Uncertain

0.34

BayesDel_addAF

Benign

-0.083

BayesDel_noAF

Benign

-0.13

CADD

Pathogenic

(source)

DANN

Pathogenic

1.0

DEOGEN2

Benign

0.051

T;.

Eigen

Uncertain

0.26

Eigen_PC

Uncertain

0.33

FATHMM_MKL

Pathogenic

0.99

LIST_S2

Uncertain

0.90

D;D

M_CAP

Uncertain

0.19

MetaRNN

Benign

0.31

T;T

MetaSVM

Benign

-0.90

MutationAssessor

Uncertain

2.1

M;.

PhyloP100

6.2

PrimateAI

Pathogenic

0.84

PROVEAN

Benign

-1.5

N;N

REVEL

Benign

0.23

Sift

Uncertain

0.0020

D;D

Sift4G

Uncertain

0.023

D;D

Polyphen

0.91

P;.

Vest4

0.56

MVP

0.75

MPC

1.7

ClinPred

0.27

GERP RS

4.1

Varity_R

0.15

gMVP

0.54

Mutation Taster

=88/12

polymorphism

(source)

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

Publications

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over