chr6-41033049-G-C

Position:

• chr6-41033049-G-C

Variant summary

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

The NM_173561.3(UNC5CL):​c.784C>G​(p.His262Asp) variant causes a missense change. The variant allele was found at a frequency of 0.00000137 in 1,459,946 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.0000014 (0 hom.)
• Consequence: UNC5CL NM_173561.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 4.85

Genes affected

UNC5CL (HGNC:21203): (unc-5 family C-terminal like) Enables peptidase activity. Acts upstream of or within positive regulation of I-kappaB kinase/NF-kappaB signaling and positive regulation of JNK cascade. Located in membrane. [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
UNC5CL	NM_173561.3	c.784C>G	p.His262Asp	missense_variant	4/9	ENST00000244565.8	NP_775832.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
UNC5CL	ENST00000244565.8	c.784C>G	p.His262Asp	missense_variant	4/9	1	NM_173561.3	ENSP00000244565	P1
UNC5CL	ENST00000373164.1	c.784C>G	p.His262Asp	missense_variant	3/8	1		ENSP00000362258	P1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 0.00000137 AC: 2 AN: 1459946 Hom.: 0 Cov.: 32 AF XY: 0.00 AC XY: 0 AN XY: 726096

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.: 33

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 16, 2021

The c.784C>G (p.H262D) alteration is located in exon 4 (coding exon 3) of the UNC5CL gene. This alteration results from a C to G substitution at nucleotide position 784, causing the histidine (H) at amino acid position 262 to be replaced by an aspartic acid (D). 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	Pathogenic	0.73
BayesDel_addAF	Uncertain	0.072	D
BayesDel_noAF	Benign	-0.13
CADD	Benign	23
DANN	Uncertain	0.99
DEOGEN2	Benign	0.0026	T;T
Eigen	Benign	-0.15
Eigen_PC	Benign	0.044
FATHMM_MKL	Uncertain	0.89	D
LIST_S2	Benign	0.69	T;.
M_CAP	Benign	0.0086	T
MetaRNN	Uncertain	0.59	D;D
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	1.4	L;L
MutationTaster	Benign	0.97	D;D
PrimateAI	Uncertain	0.57	T
PROVEAN	Benign	0.42	N;N
REVEL	Benign	0.16
Sift	Benign	0.22	T;T
Sift4G	Uncertain	0.021	D;D
Polyphen		0.31	B;B
Vest4		0.81
MutPred		0.45		Loss of sheet (P = 0.0817);Loss of sheet (P = 0.0817);
MVP		0.40
MPC		0.35
ClinPred		0.66	D
GERP RS		5.5
Varity_R		0.13
gMVP		0.37

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: chr6-41000788;