Genetic Variant TMCC2:p.Arg5Lys (chr1-205228578-G-A) – ACMG Classification: Likely_benign (-6 pts)

Variant summary

Our verdict is Likely benign. The variant received -6 ACMG points: 0P and 6B. BP4_StrongBP6_Moderate

The NM_014858.4(TMCC2):c.14G>A(p.Arg5Lys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000018 in 1,610,558 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 16/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★).

Frequency

Genomes: 𝑓 0.0000066 ( 0 hom., cov: 32)

Exomes 𝑓: 0.000019 ( 0 hom. )

Consequence

TMCC2
NM_014858.4 missense

Scores

Clinical Significance

Likely benign criteria provided, single submitter B:1

Conservation

PhyloP100: 0.917

Publications

0 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:

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ACMG classification

Classification was made for transcript

Our verdict: Likely_benign. The variant received -6 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.039760053).

BP6

Variant 1-205228578-G-A is Benign according to our data. Variant chr1-205228578-G-A is described in ClinVar as Likely_benign. ClinVar VariationId is 3326562.Status of the report is criteria_provided_single_submitter, 1 stars.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_014858.4. 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
	TMCC2	NM_014858.4	MANE Select	c.14G>A	p.Arg5Lys	missense	Exon 1 of 5	NP_055673.2	O75069-1

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
TMCC2	ENST00000358024.8	TSL:1 MANE Select	c.14G>A	p.Arg5Lys	missense	Exon 1 of 5	ENSP00000350718.3	O75069-1
TMCC2	ENST00000962349.1		c.14G>A	p.Arg5Lys	missense	Exon 2 of 6	ENSP00000632408.1
TMCC2	ENST00000907462.1		c.14G>A	p.Arg5Lys	missense	Exon 1 of 4	ENSP00000577521.1

Frequencies

GnomAD3 genomes

AF:

0.00000657

AC:

AN:

152158

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.000193

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00

Gnomad OTH

AF:

0.00

GnomAD4 exome

AF:

0.0000192

AC:

AN:

1458400

Hom.:

Cov.:

AF XY:

0.00000966

AC XY:

AN XY:

724920

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

33420

American (AMR)

AF:

0.00

AC:

AN:

44592

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26072

East Asian (EAS)

AF:

0.000707

AC:

AN:

39596

South Asian (SAS)

AF:

0.00

AC:

AN:

86108

European-Finnish (FIN)

AF:

0.00

AC:

AN:

52762

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5758

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

1109848

Other (OTH)

AF:

0.00

AC:

AN:

60244

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.471

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome 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

GnomAD4 genome

AF:

0.00000657

AC:

AN:

152158

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

74324

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

41436

American (AMR)

AF:

0.00

AC:

AN:

15286

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3472

East Asian (EAS)

AF:

0.000193

AC:

AN:

5178

South Asian (SAS)

AF:

0.00

AC:

AN:

4826

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10616

Middle Eastern (MID)

AF:

0.00

AC:

AN:

316

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

68028

Other (OTH)

AF:

0.00

AC:

AN:

2088

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.575

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Alfa

AF:

0.00

Hom.:

ClinVar

ClinVar submissions

Significance:Likely benign

Revision:criteria provided, single submitter

View on ClinVar

Pathogenic

VUS

Benign

Condition

not specified (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.060

BayesDel_addAF

Benign

-0.28

BayesDel_noAF

Benign

-0.64

CADD

Benign

(source)

DANN

Benign

0.94

DEOGEN2

Benign

0.0097

Eigen

Benign

-0.75

Eigen_PC

Benign

-0.56

FATHMM_MKL

Benign

0.070

LIST_S2

Benign

0.47

M_CAP

Benign

0.0062

MetaRNN

Benign

0.040

MetaSVM

Benign

-1.1

MutationAssessor

Benign

-0.69

PhyloP100

0.92

PrimateAI

Benign

0.48

PROVEAN

Benign

0.16

REVEL

Benign

0.037

Sift

Benign

1.0

Sift4G

Benign

1.0

Polyphen

0.0

Vest4

0.11

MutPred

0.27

Gain of ubiquitination at R5 (P = 0.0037)

MVP

0.24

MPC

0.59

ClinPred

0.071

GERP RS

1.1

PromoterAI

-0.0078

Neutral

(source)

Varity_R

0.047

gMVP

0.27

Mutation Taster

=96/4

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

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over