chr7-19725688-C-A

Position:

• chr7-19725688-C-A

Variant summary

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

The NM_001363562.2(TMEM196):​c.285G>T​(p.Lys95Asn) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000137 in 1,461,588 control chromosomes in the GnomAD database, with no homozygous occurrence. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000014 (0 hom.)
• Consequence: TMEM196 NM_001363562.2 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 2.33

Genes affected

TMEM196 (HGNC:22431): (transmembrane protein 196) Predicted to be integral component of membrane. [provided by Alliance of Genome Resources, Apr 2022]

LOC107986774 (HGNC:):

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
TMEM196	NM_001363562.2	c.285G>T	p.Lys95Asn	missense_variant	3/5	ENST00000405844.6	NP_001350491.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
TMEM196	ENST00000405844.6	c.285G>T	p.Lys95Asn	missense_variant	3/5	5	NM_001363562.2	ENSP00000385087.2
TMEM196	ENST00000405764.7	c.285G>T	p.Lys95Asn	missense_variant	3/4	1		ENSP00000384234.3
TMEM196	ENST00000422233.5	c.81G>T	p.Lys27Asn	missense_variant	3/5	5		ENSP00000414247.1
TMEM196	ENST00000493519.2	c.81G>T	p.Lys27Asn	missense_variant	3/4	5		ENSP00000438368.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000137 AC: 2 AN: 1461588 Hom.: 0 Cov.: 31 AF XY: 0.00000138 AC XY: 1 AN XY: 727052

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000180

Gnomad4 OTH exome AF: 0.00

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

Sep 20, 2024

The c.285G>T (p.K95N) alteration is located in exon 3 (coding exon 3) of the TMEM196 gene. This alteration results from a G to T substitution at nucleotide position 285, causing the lysine (K) at amino acid position 95 to be replaced by an asparagine (N). 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
BayesDel_addAF	Benign	-0.028	T
BayesDel_noAF	Benign	-0.28
CADD	Benign	22
DANN	Uncertain	1.0
Eigen	Uncertain	0.42
Eigen_PC	Uncertain	0.42
FATHMM_MKL	Uncertain	0.94	D
LIST_S2	Uncertain	0.90	D;D;D;D;D
M_CAP	Benign	0.013	T
MetaRNN	Uncertain	0.63	D;D;D;D;D
MetaSVM	Benign	-0.53	T
PrimateAI	Uncertain	0.64	T
PROVEAN	Uncertain	-3.6	D;D;D;D;D
REVEL	Benign	0.15
Sift	Pathogenic	0.0	D;D;D;D;D
Sift4G	Pathogenic	0.0	D;D;D;D;D
Polyphen		0.99	.;D;.;.;.
Vest4		0.75
MutPred		0.30		Gain of ubiquitination at K96 (P = 0.0413);Gain of ubiquitination at K96 (P = 0.0413);.;.;.;
MVP		0.095
MPC		0.025
ClinPred		0.99	D
GERP RS		4.9
gMVP		0.23

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

No publications associated with this variant yet.

Other links and lift over

hg19: chr7-19765311; COSMIC: COSV101337519;