chr20-36786567-C-T

Variant names:

• chr20-36786567-C-T
• rs749999565
• NM_080627.4:c.4904G>A

Variant summary

Our verdict is Uncertain significance. The variant received 2 ACMG points: 2P and 0B. PM2

The NM_080627.4(MTCL2):​c.4904G>A​(p.Arg1635His) variant causes a missense change. The variant allele was found at a frequency of 0.00000774 in 1,550,916 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.0000066 (0 hom., cov: 31)
  • Exomes 𝑓: 0.0000079 (0 hom.)
• Consequence: MTCL2 NM_080627.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 5.55
• Publications: 0 publications found

Genes affected

MTCL2 (HGNC:16111): (microtubule crosslinking factor 2) Predicted to be involved in insulin receptor signaling pathway; negative regulation of gluconeogenesis; and regulation of autophagy. Located in extracellular space. [provided by Alliance of Genome Resources, Apr 2022]

ACMG classification

Our verdict: Uncertain_significance. The variant received 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_080627.4. 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
	MTCL2	NM_080627.4	MANE Select	c.4904G>A	p.Arg1635His	missense	Exon 15 of 15	NP_542194.2	O94964-2
	MTCL2	NM_199181.3		c.2993+7808G>A		intron	N/A	NP_954650.2	X6R3R3

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	MTCL2	ENST00000237536.9	TSL:5 MANE Select	c.4904G>A	p.Arg1635His	missense	Exon 15 of 15	ENSP00000237536.4	O94964-2
	MTCL2	ENST00000938705.1		c.4841G>A	p.Arg1614His	missense	Exon 14 of 14	ENSP00000608764.1
	MTCL2	ENST00000279034.10	TSL:5	c.2993+7808G>A		intron	N/A	ENSP00000279034.5	X6R3R3

Frequencies

GnomAD3 genomes AF: 0.00000658 AC: 1 AN: 151982 Hom.: 0 Cov.: 31

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: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000147

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.00000655 AC: 1 AN: 152602 AF XY: 0.0000123

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: 0.0000170

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000786 AC: 11 AN: 1398934 Hom.: 0 Cov.: 33 AF XY: 0.00000870 AC XY: 6 AN XY: 689914

African (AFR) AF: 0.00 AC: 0 AN: 31594

American (AMR) AF: 0.00 AC: 0 AN: 35702

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25182

East Asian (EAS) AF: 0.00 AC: 0 AN: 35736

South Asian (SAS) AF: 0.0000252 AC: 2 AN: 79232

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 48870

Middle Eastern (MID) AF: 0.000176 AC: 1 AN: 5688

European-Non Finnish (NFE) AF: 0.00000741 AC: 8 AN: 1078936

Other (OTH) AF: 0.00 AC: 0 AN: 57994

GnomAD4 genome AF: 0.00000658 AC: 1 AN: 151982 Hom.: 0 Cov.: 31 AF XY: 0.0000135 AC XY: 1 AN XY: 74220

⚠️ The allele balance in gnomAD version 4 Genomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.00 AC: 0 AN: 41378

American (AMR) AF: 0.00 AC: 0 AN: 15260

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

East Asian (EAS) AF: 0.00 AC: 0 AN: 5166

South Asian (SAS) AF: 0.00 AC: 0 AN: 4826

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10586

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

European-Non Finnish (NFE) AF: 0.0000147 AC: 1 AN: 67992

Other (OTH) AF: 0.00 AC: 0 AN: 2084

⚠️ The allele balance in gnomAD version 4 Genomes is significantly skewed from the expected value of 0.5. (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

Alfa AF: 0.0000310 Hom.: 0

Bravo AF: 0.00000756

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	0.14
BayesDel_addAF	Uncertain	0.040	T
BayesDel_noAF	Benign	-0.16
CADD	Pathogenic	29
DANN	Pathogenic	1.0
Eigen	Uncertain	0.36
Eigen_PC	Uncertain	0.43
FATHMM_MKL	Benign	0.66	D
LIST_S2	Uncertain	0.92	D
M_CAP	Benign	0.029	D
MetaRNN	Uncertain	0.51	D
MetaSVM	Benign	-0.82	T
PhyloP100		5.5
PrimateAI	Uncertain	0.60	T
PROVEAN	Benign	-2.0	N
REVEL	Benign	0.15
Sift	Uncertain	0.020	D
Sift4G	Pathogenic	0.0	D
Vest4		0.66
MutPred		0.49		Loss of MoRF binding (P = 0.0056)
MVP		0.18
MPC		2.4
ClinPred		0.98	D
GERP RS		5.1
gMVP		0.34
Mutation Taster		=84/16	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: rs749999565; hg19: chr20-35414970;