2-168765723-C-T

Position:

• chr2-168765723-C-T

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_203463.3(CERS6):​c.977C>T​(p.Ala326Val) variant causes a missense change. The variant allele was found at a frequency of 0.000000685 in 1,460,904 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 6.8e-7 (0 hom.)
• Consequence: CERS6 NM_203463.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 6.14

Genes affected

CERS6 (HGNC:23826): (ceramide synthase 6) Enables sphingosine N-acyltransferase activity. Involved in ceramide biosynthetic process. Located in membrane. [provided by Alliance of Genome Resources, Apr 2022]

ACMG classification

Verdict is Uncertain_significance. Variant got 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.24600077).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
CERS6	NM_203463.3	c.977C>T	p.Ala326Val	missense_variant	9/10	ENST00000305747.11
CERS6	NM_001256126.2	c.977C>T	p.Ala326Val	missense_variant	9/11
CERS6	XM_017003749.3	c.554C>T	p.Ala185Val	missense_variant	6/8
CERS6	XM_005246440.6	c.401C>T	p.Ala134Val	missense_variant	6/8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
CERS6	ENST00000305747.11	c.977C>T	p.Ala326Val	missense_variant	9/10	2	NM_203463.3	A1
CERS6	ENST00000392687.4	c.977C>T	p.Ala326Val	missense_variant	9/11	1		P4

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 6.85e-7 AC: 1 AN: 1460904 Hom.: 0 Cov.: 30 AF XY: 0.00000138 AC XY: 1 AN XY: 726652

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: 9.00e-7

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

Dec 19, 2023

The c.977C>T (p.A326V) alteration is located in exon 9 (coding exon 9) of the CERS6 gene. This alteration results from a C to T substitution at nucleotide position 977, causing the alanine (A) at amino acid position 326 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	Benign	0.22
BayesDel_addAF	Benign	-0.13	T
BayesDel_noAF	Benign	-0.42
CADD	Uncertain	23
DANN	Uncertain	0.98
DEOGEN2	Benign	0.11	T;.
Eigen	Benign	-0.015
Eigen_PC	Benign	0.19
FATHMM_MKL	Uncertain	0.97	D
LIST_S2	Uncertain	0.91	D;D
M_CAP	Benign	0.019	T
MetaRNN	Benign	0.25	T;T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	1.5	L;L
MutationTaster	Benign	1.0	D;D
PrimateAI	Uncertain	0.60	T
PROVEAN	Benign	-1.3	N;N
REVEL	Benign	0.13
Sift	Benign	0.56	T;T
Sift4G	Benign	1.0	T;T
Polyphen		0.050	B;.
Vest4		0.40
MutPred		0.42		Gain of MoRF binding (P = 0.0975);Gain of MoRF binding (P = 0.0975);
MVP		0.093
MPC		0.25
ClinPred		0.83	D
GERP RS		5.6
Varity_R		0.22
gMVP		0.70

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.040		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: chr2-169622233;