19-41848969-T-G

Position:

• chr19-41848969-T-G

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 2P and 0B. PM2

The NM_001040283.3(DMRTC2):​c.622T>G​(p.Phe208Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: DMRTC2 NM_001040283.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 2.31

Genes affected

DMRTC2 (HGNC:13911): (DMRT like family C2) Enables sequence-specific double-stranded DNA binding activity. Predicted to be involved in germ cell development; regulation of transcription by RNA polymerase II; and sex differentiation. Predicted to act upstream of or within male gamete generation and positive regulation of histone H3-K9 methylation. Predicted to be located in XY body. Predicted to be part of chromatin. Predicted to be active in nucleus. [provided by Alliance of Genome Resources, Apr 2022]

ACMG classification

Verdict is Uncertain_significance. Variant got 2 ACMG points.

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

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
DMRTC2	NM_001040283.3	c.622T>G	p.Phe208Val	missense_variant	5/9	ENST00000269945.8	NP_001035373.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
DMRTC2	ENST00000269945.8	c.622T>G	p.Phe208Val	missense_variant	5/9	1	NM_001040283.3	ENSP00000269945	P1
DMRTC2	ENST00000596827.5	c.622T>G	p.Phe208Val	missense_variant	5/8	2		ENSP00000469525
DMRTC2	ENST00000601660.5	c.662T>G	p.Leu221Arg	missense_variant, NMD_transcript_variant	5/7	2		ENSP00000472159

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

May 28, 2024

The c.622T>G (p.F208V) alteration is located in exon 5 (coding exon 4) of the DMRTC2 gene. This alteration results from a T to G substitution at nucleotide position 622, causing the phenylalanine (F) at amino acid position 208 to be replaced by a valine (V). 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	0.36
BayesDel_addAF	Benign	-0.0082	T
BayesDel_noAF	Benign	-0.25
CADD	Benign	22
DANN	Uncertain	0.98
DEOGEN2	Benign	0.22	.;T
Eigen	Uncertain	0.34
Eigen_PC	Uncertain	0.34
FATHMM_MKL	Uncertain	0.86	D
LIST_S2	Benign	0.71	T;T
M_CAP	Benign	0.047	D
MetaRNN	Uncertain	0.65	D;D
MetaSVM	Benign	-0.73	T
MutationAssessor	Uncertain	2.4	.;M
MutationTaster	Benign	0.83	D
PrimateAI	Uncertain	0.56	T
PROVEAN	Benign	-1.5	.;N
REVEL	Benign	0.17
Sift	Uncertain	0.0010	.;D
Sift4G	Benign	0.39	T;T
Polyphen		1.0	D;D
Vest4		0.60
MutPred		0.15		Gain of glycosylation at S204 (P = 0.0925);Gain of glycosylation at S204 (P = 0.0925);
MVP		0.22
MPC		0.49
ClinPred		0.95	D
GERP RS		5.3
Varity_R		0.34
gMVP		0.42

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		Details are displayed if max score is > 0.2

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

Publications

No publications associated with this variant yet.

Other links and lift over

hg19: chr19-42353037;